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Curr Opin Investig Drugs, 2004 Feb, 5(2), 146 - 53
Fatty acid biosynthesis as a target for novel antibacterials; Heath RJ et al.; The bacterial fatty acid synthesis pathway has significant potential as a target for the development of novel antibacterials . The pathway has been extensively studied in Escherichia coli, the crystal structures of the compounds involved are known and homologous genes are readily identified in the genomes of important pathogens . The currently used drugs triclosan and isoniazid are known to target one step in the pathway . Other experimental compounds such as thiolactomycin and cerulenin effectively inhibit other steps . These known pathway inhibitors are reviewed and the areas for potential future developments are explored.

Nucleosides Nucleotides Nucleic Acids, 2004, 23(1-2), 161 - 70
Synthesis and biological activity of 5-fluorotubercidin; Wang X et al.; The electrophilic fluorination of 4-chloropyrrolo{2,3-d}pyrimidine (1) was studied culminating a 59% conversion of compound 1 to 4-chloro-5-fluoropyrrolo{2,3-d}pyrimidine (2) using Selectfluor . This transformation proceeded via the 4-chloro-5,6-dihydro-5-fluoro-6-hydroxypyrrolo{2,3-d}pyrimidine (3) in a 9:1 trans:cis ratio . The trans isomer of compound 3 was studied by 1H NMR and 19F NMR, and the 5-H tautomer (4) was observed as another intermediate . A modified Vorbruggen procedure of compound 2 and tetra-O-acetylribose gave 4-chloro-5-fluoro-7-(2,3,5,-tri-O-benzoyl-beta-D-ribofuranosyl)pyrrolo{2,3-d}pyrimidine (6) in a 65% yield . Treatment of compound 6 with ammonia (l) in dioxane gave 5-fluorotubercidin (7) . No antibacterial activity was observed . An MTT assay (Promega) against Huh-7 liver cells, normal mouse spleen cells stimulated with Con A (a T-cell mitogen), and normal mouse spleen stimulated with LPS (a B-cell mitogen) showed no significant toxicity . Increased activity of 7 over tubercidin was observed against L-1210 cells and toxicity in fibroblast cells was reduced.

Amino Acids, 2004 Mar, 26(2), 139 - 46 Epub 2003 Dec 31.
Synthesis of novel 3-pyridinecarbonitriles with amino acid function and their fluorescence properties; Girgis AS et al.; A variety of N-{(4,6-diaryl-3-pyridinecarbonitrile)-2-yl} amino acid esters 2-4 were synthesized through the reaction of 2-bromo-3-pyridinecarbonitriles 1 with the appropriate alpha-amino acid ester hydrochloride in refluxing dioxane in the presence of triethylamine as dehydrohalogenating agent . Similarly, N'-glycylglycine analogues 5 were obtained through the reaction of 1 with the dipeptide ester . On the other hand, attempts were made towards the construction of amino acid derivatives 7 through the reaction of 1 with aqueous solution alpha-amino acids 6 in refluxing pyridine, but were unsuccessful, and instead the unexpected 2-amino-3-pyridinecarbonitriles 8 were isolated . The fluorescence properties of the newly synthesized pyridines 2-5 were evaluated . Some of the prepared compounds show considerable antibacterial activity.

Nat Rev Microbiol, 2003 Oct, 1(1), 65 - 70
Where will new antibiotics come from?
Walsh C.
There is a constant need for new antibacterial drugs owing to the inevitable development of resistance that follows the introduction of antibiotics to the clinic . When a new class of antibiotic is introduced, it is effective at first, but will eventually select for survival of the small fraction of bacterial populations that have an intrinsic or acquired resistance mechanism . Pathogens that are resistant to multiple drugs emerge around the globe, so how robust are antibiotic discovery processes?

Clin Ther, 2004 Feb, 26(2), 191 - 6
Topical antibacterial therapy for mycobacterial keratitis: potential for surgical prophylaxis and treatment; Abshire R et al.; BACKGROUND: Mycobacterium chelonae and Mycobacterium fortuitum are the 2 most commonly implicated species of nontuberculous mycobacteria in cases of bacterial keratitis . OBJECTIVES: This article summarizes available data on the in vitro antibacterial activity against M chelonae or M fortuitum of 2 agents-amikacin and clarithromycin-that have been used in the treatment of bacterial keratitis . In addition, the article reviews the in vitro activity of 5 commercially available topical ocular fluoro-quinolones (in order of availability, ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin) that may have potential in the surgical prophylaxis and treatment of keratitis caused by M chelonae or M fortuitum . METHODS: A search of the English-language literature indexed on the MEDLINE, Life Sciences, EMBASE, BIOSIS, and Pharmaprojects databases from 1966 to October 7, 2003, was conducted using the terms Mycobacterium chelonae, Mycobacterium fortuitum, bacterial keratitis, topical antibiotic therapy, ocular infection-mycobacteria, and LASIK infections . Data on the minimum concentrations at which 90% of isolates were inhibited (MIC(90)s) were reviewed and compared . RESULTS: In the literature reviewed, the MIC(90) against M fortuitum was from 1 to 16 microg/mL for amikacin, from </=2 to >/=8 microg/mL for clarithromycin, from 0.1 to 1 microg/mL for ciprofloxacin, from 0.5 to 3.13 microg/mL for ofloxacin, and </=2 microg/mL for levofloxacin . The results were similar against M chelonae . The fourth-generation fluoroquinolones-gatifloxacin and moxifloxacin-had similar MIC(90)s against M fortuitum (both, 0.2 to 1 microg/mL); however, moxifloxacin had greater activity than gatifloxacin against M chelonae (minimum inhibitory concentration range: moxifloxacin, </=1 to 1.6 microg/mL; gatifloxacin, 3.2 to 6.25 microg/mL) . CONCLUSIONS: Topical fluoroquinolones may be beneficial for ocular surgical prophylaxis and for the treatment of keratitis caused by M chelonae or M fortuitum . Based on their reported MIC(90)s, none of the antibacterials reviewed had greater in vitro activity than moxifloxacin . In addition, moxifloxacin had greater in vitro activity than gatifloxacin against M chelonae, one of the predominant nontuberculous mycobacterial species involved in bacterial keratitis . Pending the conduct of controlled clinical studies, these findings suggest that moxifloxacin may have utility in the prevention and treatment of atypical mycobacterial keratitis.

Arch Pharm (Weinheim), 2004 Mar, 337(3), 164 - 70
Synthesis and biological testing of novel analogues of sydnone as potential antibacterial agents; Moustafa MA et al.; Several series of 3-phenylsydnone derivatives conjugated to well-known moieties with antibacterial activity were synthesized via several routes . These derivatives include 3-cyano-2-oxopyridine, 2-amino-3-cyanopyridine, 2-arylidene-1-ethylidenehydrazine and 2-aroyl-1-ethylidenehydrazine moieties . Thus, the key intermediate 3-(4-acetylphenyl)sydnone (3) was allowed to react with the appropriate aldehyde, ethyl cyanoacetate or malononitrile in presence of excess ammonium acetate in two steps (method 1) or through a one-pot reaction technique (methods 2 and 3) to give the corresponding sydnone derivatives 5 and 6, respectively . Moreover, condensation of compound 3 with hydrazine hydrate followed by the reaction with the appropriate aldehyde, mono- and dicarboxylic acid hydrazide yielded the corresponding sydnone derivatives 8, 9 and 10, respectively . Most of the synthesized compounds were screened for their in vitro antibacterial activity against various pathogenic organisms of both Gram-positive and Gram-negative bacteria . The minimum inhibitory concentrations (MICs) were determined using agar dilution method.

Int J Antimicrob Agents, 2004 Mar, 23 Suppl 1, S83 - 7
Single-drug or combined antibacterial therapy in the treatment of patients with chronic prostatitis and Chlamydia trachomatis?
Smelov V, Gorelov A, Smelova N, Krylova T.
The efficacy of antibacterial combinations as compared with single-drug treatment in 57 patients with chronic prostatitis and Chlamydia trachomatis was investigated in this study.

Int J Antimicrob Agents, 2004 Mar, 23 Suppl 1, S79 - 82
Azithromycin treatment follow-up: antibacterial susceptibility of Chlamydia trachomatis in patients with chronic prostatitis; Smelov V et al.; The antibacterial susceptibility of Chlamydia trachomatis in 138 patients with chronic prostatitis (CP) and clinical failures after antibacterial treatment with azithromycin (AZI) were investigated . Azithromycin was not found to be top-of-the-line drug in the follow-up treatment, showing only average results in vitro . The investigation of the susceptibility of chlamydia to antibiotics in causes of chronic prostatitis is highly recommended.

Toxicon, 2004 Mar 1, 43(3), 311 - 8
Anti-Plasmodium properties of group IA, IB, IIA and III secreted phospholipases A2 are serum-dependent; Guillaume C et al.; Antibacterial, antiparasitidal and antiviral properties have recently been attributed to members of the secreted phospholipases A(2) (sPLA(2)s) superfamily . Seven sPLA(2)s from groups IA, IB, IIA and III, were tested here in different culture conditions for inhibition of the in vitro intraerythrocytic development of Plasmodium falciparum, the causative agent of the most severe form of human malaria . In the presence of human serum, all sPLA(2)s were inhibitory, with three out of seven exhibiting IC(50)<0.1 nM . In all cases, inhibition could be induced by enzymatic pre-treatment of the serum . By contrast, no effect was observed when parasites were grown in a semi-defined medium (AlbuMAX II) devoid of lipoproteins and containing 10 times less phospholipids than the medium with human serum, strongly suggesting that hydrolysis of serum generating toxic lipid by-products, rather than a direct interaction of the sPLA(2) with the infected erythrocyte, is a general feature of the anti-Plasmodium properties of sPLA(2)s . Furthermore, in serum, six out of the seven sPLA(2)s were toxic against both trophozoite and schizont stages of the parasite development, contrasting with the trophozoite-selective bee venom enzyme's toxicity . Deciphering the molecular mechanisms at play in the phenotypic singularity of the bee venom enzyme toxicity might offer new prospects in antimalarial fight.

Pharm Res, 2004 Feb, 21(2), 330 - 8
Effect of cisplatin-induced acute renal failure on bioavailability and intestinal secretion of quinolone antibacterial drugs in rats; Yamaguchi H et al.; PURPOSE: The aim of this study was to clarify the effects of renal failure on intestinal secretion of quinolone antibacterial drugs . METHODS: Pharmacokinetics of grepafloxacin, levofloxacin, and ciprofloxacin in cisplatin-induced acute renal failure (ARF) rats were evaluated, and intestinal and biliary clearance studies were examined . Transport experiments using culture cells were performed . RESULTS: The bioavailability of grepafloxacin in ARF rats was 1.2-fold higher than that in normal rats . On the other hand, the bioavailability of ciprofloxacin in ARF rats was markedly decreased to half of that in normal rats, and that of levofloxacin was not changed . Intestinal clearance of grepafloxacin in ARF rats was 75% of that in normal rats, whereas that of ciprofloxacin was 1.4-fold higher than in normal rats, and that of levofloxacin was comparable between normal and ARF rats . Transport experiments using P-glycoprotein-expressing LLC-GA5-COL150 cells and human intestinal Caco-2 cells suggested that grepafloxacin and levofloxacin were substrates of P-glycoprotein and that ciprofloxacin was not, and that intestinal secretion of ciprofloxacin was mediated by a specific transport system distinct from organic cation and anion transporters and multidrug resistance-associated protein 2 . CONCLUSIONS: Cisplatin-induced ARF differentially modulated the bioavailability and intestinal secretion of quinolones in rats.

Fitoterapia, 2004 Mar, 75(2), 228 - 30
Antibacterial compounds from the seeds of Psoralea corylifolia; Khatune NA et al.; Psoralidin, bakuchicin, psoralin and angelicin, isolated from the seeds of Psoralea corylifolia, showed significant antibacterial activities against a number of Gram (+) and Gram (-) bacteria.

Fitoterapia, 2004 Mar, 75(2), 204 - 8
Antibacterial activities of some constituents from oleo-gum-resin of Commiphora mukul; Saeed MA et al.; The essential oil, chloroform extract and seven sesquiterpenoids compounds newly isolated from the oleo-gum-resin of Commiphora mukul showed a wide range of inhibiting activity against both Gram (+) and Gram (-) bacteria.

J Agric Food Chem, 2004 Mar 24, 52(6), 1514 - 9
Relationship between antibacterial activity of (+)-catechin derivatives and their interaction with a model membrane; Kajiya K et al.; (+)-Catechin derivatives with different alkyl chain lengths were synthesized from (+)-catechin and various straight chain alkylaldehydes in the presence of methyl mercaptan, and their antibacterial activities against Gram-positive bacteria were evaluated . The antibacterial activity increased markedly with elongation of the alkyl chain lengths of the derivatives and reached a maximum at a chain of four to seven carbons . Subsequently, interaction of the (+)-catechin derivatives with a model membrane using liposome was investigated . The derivatives with a chain of three carbons or more were found to have very strong affinity for the membrane . The injury action of the derivatives against the membrane was examined with liposome in which calcein was enclosed as a fluorescent indicator . The leakage was observed in the derivatives with chain lengths of four carbons or more . Particularly the derivatives with chains longer than five carbons are considered to destroy the liposome membrane judging from the degree of the fluorescent leakage . These results implied that the lipophilicity and disrupting ability of the (+)-catechin derivatives to the liposome membrane participate in their antibacterial activity.

Vestn Otorinolaringol, 2004, (1), 49 - 50
{Comparative efficacy and safety of amoxiclav (amoxicillin clavulanate) and ampicillin in the treatment of acute bacterial sinusitis}; Kriukov AI et al.; Efficacy and safety of amoxiclav (amoxicillin clavulanate) and ampicillin were studied in antibacterial therapy of acute sinusitis . Antibacterial efficacy of amoxiclav in acute sinusitis reached 100% . Its safety was good . Antibacterial efficacy of ampicillin was 76%; 24% patients retained symptoms of the disease, x-ray picture of sinusitis . Its toxicity was higher.

Vestn Otorinolaringol, 2004, (1), 39 - 41
{Pre- and intraoperative preparation of patients with pyoinflammatory diseases of the ear, pharynx and paranasal sinuses}; Kriukov AI et al.; The authors consider the problems of effective general and local antibiotic therapy regarding most frequently occurring now causative agents and doses of antibacterial drugs . Combined use of antibacterial drugs and immunostimulators is analysed as antibacterial drugs deteriorate nonspecific immunity.

Vestn Otorinolaringol, 2004, (1), 35 - 8
{Current antibacterial therapy of acute otitis media}; Turovskii AB et al.; General approaches to general and local therapy of acute otitis media are validated and schemes of antibacterial treatment of this disease are proposed.

Vestn Otorinolaringol, 2004, (1), 33 - 4
{Bacterial contamination of the maxilla after radical surgical treatment}; Pal'chun VT et al.; Qualitative and quantitative examinations of the microflora in a postoperative cavity of 62 patients early after radical surgery on the maxilla with opening of the ethmoidal labyrinth have found that in spite of a noticeable antibacterial effect of the operation pyoinflammatory process in the wound is possible . Treatment basing on bacteriological findings is recommended.

Vestn Otorinolaringol, 2004, (1), 28 - 32
{The role of chlamydial infection in development of acute respiratory diseases in children}; Savenkova MS et al.; The examination of 245 children with respiratory diseases has detected chlamydia in 45 (18.4%) of them . Chlamydial species were identified and clinical symptoms of acute respiratory diseases (ARD) of chlamydial etiology are described . Five serological groups of patients depending on the presence or absence of chlamydial infection markers were recognized . Antibacterial drug treatment showed that most effective were sumamed, rulid and clindamycin . Long-term outcomes in relation to the kind of treatment are analysed.

Vestn Otorinolaringol, 2004, (1), 5 - 14
{Effective antibacterial therapy in otorhinolaryngology: bacteriological rationale}; Zhukhovitskii VG; The article presents current views on etiopathogenesis of the diseases associated with contamination with microorganisms; reviews inflammatory ENT diseases in terms of current literature on clinical microbiology of these diseases; characterizes microorganisms more or less specific for each relevant nosological entity; analyses basic groups of antibacterial drugs with formulation of bacteriologically grounded principles of initial antibacterial therapy of ENT inflammation.

Bioorg Med Chem Lett, 2004 Apr 5, 14(7), 1811 - 5
Preliminary in vitro studies on two potent, water-soluble trimethoprim analogues with exceptional species selectivity against dihydrofolate reductase from Pneumocystis carinii and Mycobacterium avium; Forsch RA et al.; 2,4-Diamino-5-{3',4'-dimethoxy-5'-(5-carboxy-1-pentynyl)}benzylpyrimidine (6) and 2,4-diamino-5-{3',4'-dimethoxy-5'-(4-carboxyphenylethynyl)benzylpyrimidine (7) were synthesized from 2,4-diamino-5-(5'-iodo-3',4'-dimethoxybenzyl)pyrimidine (9) via a Sonogashira reaction with appropriate acetylenic esters followed by saponification, and were tested as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), Mycobacterium avium (Ma), and rat in comparison with the widely used antibacterial agent 2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine (trimethoprim, TMP) . The selectivity index (SI) for each compound was calculated by dividing its 50% inhibitory concentration (IC(50)) against rat DHFR by its IC(50) against Pc, Tg, or Ma DHFR . The IC(50) of 6 against Pc DHFR was 1.0 nM, with an SI of 5000 . Compound 7 had an IC(50) of 8.2 nM against Ma DHFR, with an SI of 11000 . By comparison, the IC(50) of TMP was 12000 nM against Pc, 300 nM against Ma, and 180000 against rat DHFR . The potency and selectivity values of 6 and 7 were not as high against Tg as they were against Pc or Ma DHFR, but nonetheless exceeded those of TMP . Because of the outstanding selectivity of 6 against Pc and of 7 against Ma DHFR, these novel analogues may be viewed as promising leads for further structure-activity optimization.

Bioconjug Chem, 2004 Mar-Apr, 15(2), 333 - 43
Immobilization of a novel antibacterial agent on solid phase and subsequent isolation of EF-Tu; Deibel MR Jr et al.; Screening of our compound collection identified PNU-92560, a 2-{1,3,4}thiadiazolo{3,2-a}pyrimidine-6-carboxamide, as a novel antibacterial agent . Extensive analogue development identified that the 2-position of the thiadiazole could be functionalized with a linker that would allow the compound to be attached to a solid support . The extreme insolubility of the analogues prevented the mechanism of action for these compounds to be determined utilizing traditional methodology . The solid-supported compounds were utilized as affinity columns to identify elongation factor Tu (EF-Tu) as a putative target for this class of compounds . The activity of the compounds in a metabolic labeling experiments and in translation assay supports the identity of the target for these compounds to be EF-Tu.

Biomaterials, 2004 Aug, 25(17), 3689 - 98
Evaluation of antibiotic-loaded collagen-hyaluronic acid matrix as a skin substitute; Park SN et al.; The 1-ethyl-(3-3-dimethylaminopropyl) carbodiimide hydrochloride-crosslinked collagen-hyaluronic acid (HA) matrices containing tobramycin or ciprofloxacin as an antibiotic agent were fabricated for the control of wound contamination and characterized with respect to morphology, mechanical strength, in vitro release, antibacterial activity and cytotoxicity . For the tobramycin loaded matrix, the antibacterial capacity increased with the drug loading . Tobramycin and ciprofloxacin loaded matrices maintained their antibacterial effects for over 96 and 48 h, respectively . However, cell viability testing revealed that 0.4 mg/ml of ciprofloxacin has a cytotoxic effect on fetal human dermal fibroblasts . The effects of the bilayered collagen-HA matrices containing tobramycin and growth factors were also evaluated using an in vivo full thickness dermal defect model . Though the tobramycin incorporated collagen-HA matrix had no significant effect on wound healing compared with the control, the tobramycin incorporated matrix containing basic fibroblast growth factor or platelet-derived growth factor significantly enhanced wound healing . This study demonstrates the potential efficacy of crosslinked collagen-HA matrix containing antibiotics and growth factors for defective skin tissue replacement and infection prevention.

Peptides, 2003 Nov, 24(11), 1779 - 84
The antibacterial peptide ceratotoxin A displays alamethicin-like behavior in lipid bilayers; Saint N et al.; Ceratotoxin A (CtxA), a 36-residue alpha-helical cationic peptide isolated from the medfly Ceratitis capitata, exhibits strong antibacterial activity . To determine its mode of action against bacteria, we investigated the behavior of ceratotoxin A by incorporating it into planar lipid bilayers . Macroscopic and single channel conductance experiments showed that ceratotoxin A forms voltage-dependent ion channels in bilayers according to the barrel-stave model . The characteristics of the channel suggest that the C-terminal regions form bundles of five or six helices embedded in the membrane, such that the N-terminal moieties lie on the polar side of the lipid bilayer.

Peptides, 2003 Nov, 24(11), 1753 - 61
Membrane binding and permeation by indolicidin analogs studied by a biomimetic lipid/polydiacetylene vesicle assay; Halevy R et al.; Membrane binding and relative penetration of indolicidin analogs were studied using lipid/polydiacetylene (PDA) chromatic biomimetic membranes . Colorimetric and fluorescence analyses determined that an indolicidin analog with a proline and tryptophan residue substituted with lysines showed more pronounced bilayer surface interactions, while indolicidin and particularly an indolicidin analog in which all prolines were replaced with alanine residues exhibited deeper insertion into the lipid bilayer . The colorimetric data demonstrated that more pronounced blue-red transitions were observed when the chromatic vesicles incorporated lipopolysaccharide (LPS) within the lipid bilayer, indicating that LPS promoted preferred binding and incorporation of the peptides at the lipid/water interface . The fluorescence quenching experiments further confirmed this outcome . The results indicate that the antibacterial activity of indolicidin most likely requires initial binding to the LPS moieties within bacterial membranes, as well as disruption of the bilayer interface . The degree of hemolysis induced by the analogs, on the other hand, correlated to the extent of penetration into the hydrophobic core of the lipid assembly.

Peptides, 2003 Nov, 24(11), 1713 - 21
A peptidylprolyl cis/trans isomerase from Xenopus laevis skin: cloning, biochemical characterization and putative role in the secretion; Miele R et al.; In amphibian skin secretions, a peptidylprolyl cis/trans isomerase activity was detected . A Xenopus laevis skin cDNA coding for this protein was cloned, sequenced and over-expressed in Escherichia coli . The primary structure of the protein shows extensive similarity with members of the cyclophilin A family . Catalytic parameters of the recombinant protein are similar to those of the human enzyme . The enzymatic activity is inhibited by cyclosporin A . Data suggesting that peptidylprolyl isomerization influences the biological activity of antibacterial peptides of amphibian origin are presented, and its putative role in the defence mechanism discussed.

Bull Soc Pathol Exot, 2003 Jan, 96(5), 376 - 82
{Management of mycetoma in West-Africa}; Develoux M et al.; Mycetoma is still endemic in the northern areas of West-Africa . This infection is more common in males, rural inhabitants, between 20 and 40 years of age . Mycetoma is generally easy to identify on clinical presentation, it is a chronic subcutaneous inflammatory tumor with discharging sinuses . The commonest affected site is the foot (70%), leg, knee, thigh, hand and arm are the most frequent extrapodal localizations . Diagnosis must be confirmed by the presence of grains at direct and histological examinations . It is indispensable to distinguish actinomycetoma (caused by aerobic bacteria) and eumycetoma (caused by fungi) as their treatments are different . The main etiological agents in West-Africa: Streptomyces somaliensis, Actinomadura pelletieri, Actinomadura madurae (actinomycetes), Madurella mycetomatis and Leptosphaeria sp (fungi) can be identified in most cases by histological examination of the grain . In the West Sahelian belt actinomycetoma is more frequent than eumycetoma except in Mauritania . When a mycetoma is diagnosed it is fundamental to determine as precisely as possible the extent of the lesion . Bone involvement is the major complication and must be systematically investigated by radiology . Mycetoma has characteristic ultrasonographic features, ultrasonographic technique appears to be very useful in medical centers where no mycological tests can be done . Ultrasonography is also an accurate technique to delimit the extent of the process . Computed tomography is also sensitive to assess the extent of mycetoma in soft tissues and can detect early bone involvement but is more onerous than ultrasonography . Ketoconazole or itraconazole in combination with surgery is recommended for eumycetoma patients . Actinomycetoma responds to antibacterial agents, different therapeutic schemes can be proposed and depend on the etiological agent.

J Antibiot (Tokyo), 2003 Dec, 56(12), 1033 - 44
Novel alpha-pyrones produced by a marine Pseudomonas sp . F92S91: taxonomy and biological activities; Singh MP et al.; Inhibitors of the enzymes involved in fatty acid biosynthesis (FAB) have been reported as antibacterial agents . These include thiolactomycin, cerulenin, triclosan, diazoborine, naphthyridinones, aminopyridines and pyridoindoles . Our search for new FAB inhibitors, using a lacZ reporter cell-based screen, led to several confirmed hits . Culture F92S91, later identified as a Pseudomonas sp . based on 16S profiling, was found to produce two alpha-pyrones (I and II) and three high molecular weight peptides . The pyrones were unstable under acidic conditions, and they were rearranged into a furanone derivative (III) . Of these compounds, pyrone I was the most active with MICs (microg/ml) against B . subtilis (1 to approximately 2), MRSA (2 to approximately 4), M . catarrhalis (4) and VRE (2 to approximately 64) . Effects on macromolecular synthesis and membrane functions were tested in B . subtilis . Pyrone I nonspecifically inhibited incorporation of radiolabeled precursors into DNA, RNA and protein within 5 minutes of drug exposure, similar to that of triclosan . Both compounds also inhibited the cellular uptake of these precursors . Cerulenin did not have an effect until 30 minutes of drug treatment . Pyrone I and triclosan were membrane-active (BacLight test); however, pyrone I (at < or = 128 microg/ml concentration) was not hemolytic to human RBCs in contrast to triclosan, which was hemolytic at 16 microg/ml . These data suggest that pyrone-I, unlike triclosan, selectively affects bacterial membrane function.

Fundam Clin Pharmacol, 2003 Dec, 17(6), 691 - 701
Clarithromycin reduces Isus and Ito currents in human atrial myocytes with minor repercussions on action potential duration; Gluais P et al.; The macrolide antibacterial agent clarithromycin has been shown to cause QT interval prolongation on the electrocardiogram . In rabbit heart preparations clarithromycin (concentration dependently) lengthened the action potential duration and blocked the delayed rectifier current . The aim of the present study was to investigate the clarithromycin effects: (i) on the Ca2+ L-type and the main K+ repolarizing currents on human atrial myocytes, using whole-cell patch clamp recordings and (ii) on action potentials recorded from human atrial and ventricular myocardium using conventional microelectrodes . It has been found that (i) 10-30 microM clarithromycin reduced the sustained current Isus significantly and that a 100 microM concentration was needed to cause a significant reduction in the transient outward current Ito, whereas clarithomycin did not affect the calcium current and (ii) clarithromycin (10-100 microM) prolonged the action potential duration in atrial preparations but did not alter the different parameters of the ventricular action potential . It is concluded that clarithromycin exerts direct cardiac electrophysiological effects that may contribute to pro-arrythmic potential.

Zhongguo Zhong Yao Za Zhi, 2003 Mar, 28(3), 196 - 8
{Advance of chemical constituents and bioactivity of Saururuaceae plants}; Ma L et al.; Essential oil, flavonoids, alkaloids and lignas were isolated from Saururuaceae plants . They possesses antibacteral, antiviruses, antiinflammatory . Inhibitory of plaleted aggregation activites and exhibit significant neuroleptic activity.

Am J Ophthalmol, 2004 Mar, 137(3), 554 - 6
Ocular vaccinia following exposure to a smallpox vaccinee; Hu G et al.; PURPOSE: To describe the presentation and management of the first identified case of ocular vaccinia infection associated with the current smallpox vaccination program . DESIGN: Case report . METHODS: Vaccinia virus was isolated by cell culture of a conjunctival swab . Direct staining with fluorescein isothiocyanate-labeled vaccinia antibody and polymerase chain reaction testing confirmed the diagnosis . RESULTS: In February 2003, a 26-year-old woman developed right preseptal cellulitis and blepharoconjunctivitis following contact with a vaccinated member of the military . The preseptal cellulitis resolved with antibacterial therapy, and the conjunctival infection was treated successfully with a 14-day course of topical trifluridine and a single dose of intravenous vaccinia immune globulin . CONCLUSIONS: To facilitate rapid diagnosis and appropriate treatment, clinicians must maintain a high index of suspicion for ocular smallpox vaccine-associated adverse reactions in vaccine recipients and their close contacts.

FEBS Lett, 2004 Mar 12, 561(1-3), 181 - 5
The existence of a putative post-transcriptional regulatory element in 3'-UTR of Drosophila antibacterial peptide diptericin's mRNA; Chen HX et al.; Antibacterial peptides' genes are rapidly and transiently expressed on immune stimulation, which is the characteristic of immediate early genes . It implies post-transcriptional regulation is an important pathway in antibacterial peptides' gene expression . In a search of putative post-transcriptional regulatory elements, we found a segment of an AU-rich sequence in 3'-untranslated region (UTR) of drosophila diptericin mRNA . 3'-UTR of diptericin mRNA can be specifically bound with Elav and this binding can be competed with the typical AU-rich element (ARE) of c-fos mRNA . These results suggest that the AU-rich sequence in the 3'-UTR of diptericin mRNA may be a cis-acting element and involved in post-transcriptional regulation.

Drugs Aging, 2004, 21(4), 211 - 28
Epidemiology and management of diverticular disease of the colon; Kang JY et al.; Colonic diverticula are protrusions of the mucosa through the outer muscular layers, which are usually abnormally thickened, to form narrow necked pouches . Diverticular disease of the colon covers a wide clinical spectrum: from an incidental finding to symptomatic uncomplicated disease to diverticulitis . A quarter of patients with diverticulitis will develop potentially life-threatening complications including perforation, fistulae, obstruction or stricture . In Western countries diverticular disease predominantly affects the left colon, its prevalence increases with age and its causation has been linked to a low dietary fibre intake . Right-sided diverticular disease is more commonly seen in Asian populations and affects younger patients . Its pathogenesis and relationship to left-sided diverticular disease remains unclear . Diverticular disease of the colon is a significant cause of morbidity and mortality in the Western world and its frequency has increased throughout the whole of the 20th century . Since it is a disease of the elderly, and with an aging population, it can be expected to occupy an increasing portion of the surgical and gastroenterological workload . It is uncertain what symptoms uncomplicated diverticular disease gives rise to: there is an overlap with irritable bowel syndrome . Diagnosis is primarily by barium enema and colonoscopy, but more sophisticated imaging procedures such as computed tomography (CT) are increasingly being used to assess and treat complications such as abscess or fistula, or to provide alternative diagnoses if diverticulosis is not confirmed.Initial therapy for uncomplicated diverticulitis is supportive, including monitoring, bowel rest and antibacterials . CT is used to guide percutaneous drainage of abscesses to avoid surgery or allow it to be performed as an elective procedure . Surgery is indicated for complications of acute diverticulitis, including failure of medical treatment, gross perforation, and abscess formation that cannot be resolved by percutaneous drainage . Complications of chronic diverticulitis (fistula formation, stricture and obstruction) are also usually treated surgically . However, the indications for, and the timing and staging of operations for diverticular disease are often difficult decisions requiring sound clinical judgement . Factors such as the number of episodes of inflammation, the age of the patient, and his/her overall medical condition play a role in determining whether or not a patient should undergo surgical resection . Laparoscopic surgery may be associated with less pain, less morbidity and shorter hospital stays, but its exact role is yet to be defined . Diverticular disease of the colon is the most common cause of acute lower gastrointestinal haemorrhage, which can be massive . Although the majority of patients stop bleeding spontaneously, angiographic and surgical treatment may be required, while the place of endoscopic haemostasis remains to be established.

Immunology, 2004 Mar, 111(3), 273 - 81
Human beta-defensin-2 functions as a chemotactic agent for tumour necrosis factor-alpha-treated human neutrophils; Niyonsaba F et al.; Neutrophils are the effector cells in both innate and adaptive immunity, where they perform the functions of phagocytosis and killing of bacteria . They respond to a large number of chemoattractants, but their response to epithelial cell-derived human beta-defensins (hBD) has not been investigated . Here we report that hBD-2, but not hBD-1, is a specific chemoattractant for tumour necrosis factor (TNF)-alpha-treated human neutrophils . The optimal concentration required for maximal chemotactic activity was 5 micro g/ml . The effect of hBD-2 on neutrophils was dependent on the G-protein-phospholipase C pathway, as demonstrated by inhibition by pertussis toxin and U-73122 . In addition, ligand-receptor analysis indicated that the binding of hBD-2 was markedly inhibited by macrophage inflammatory protein (MIP)-3alpha, a specific and unique ligand for CCR6 . Furthermore, anti-CCR6 antibody could almost completely suppress the cell migration induced by hBD-2, suggesting that hBD-2 mainly utilizes CCR6 as a functional receptor . Thus, our finding that hBD-2 is a potent chemoattractant for human neutrophils through specific receptors provides a novel mechanism by which this peptide contributes to the host defence system by recruiting neutrophils to inflammation/infection sites . This also suggests an important link between epithelial cell-derived antibacterial peptides and neutrophils during infection or inflammation.

J Evol Biol, 2004 Mar, 17(2), 421 - 9
Costs of resistance: genetic correlations and potential trade-offs in an insect immune system; Cotter SC et al.; Theory predicts that natural selection will erode additive genetic variation in fitness-related traits . However, numerous studies have found considerable heritable variation in traits related to immune function, which should be closely linked to fitness . This could be due to trade-offs maintaining variation in these traits . We used the Egyptian cotton leafworm, Spodoptera littoralis, as a model system to examine the quantitative genetics of insect immune function . We estimated the heritabilities of several different measures of innate immunity and the genetic correlations between these immune traits and a number of life history traits . Our results provide the first evidence for a potential genetic trade-off within the insect immune system, with antibacterial activity (lysozyme-like) exhibiting a significant negative genetic correlation with haemocyte density, which itself is positively genetically correlated with both haemolymph phenoloxidase activity and cuticular melanization . We speculate on a potential trade-off between defence against parasites and predators, mediated by larval colour, and its role in maintaining genetic variation in traits under natural selection.

Jpn J Antibiot, 2003 Dec, 56(6), 719 - 36
{Use of the antibacterial agent levofloxacin for acute upper respiratory tract infection accompanied by fever (> or = 38 degrees C)}; Yamaguchi H et al.; The appropriate administration method of levofloxacin in relation to symptoms was investigated by following up 2,353 patients prescribed either levofloxacin (300 mg divided into 3 doses) or 400 mg (divided into 2 doses) for the treatment of acute upper respiratory tract infection accompanied by fever (temperature (> or = 38 degrees C) of suspected bacterial infection . 1) The cure rate based on body temperature as an index was significantly higher in the group administered 400 mg/day compared with the group administered 300 mg/day . No significant difference between the two regimens was observed in patients with a temperature < or = 38.5 degrees C at the start of administration, but patients with a temperature > or = 38.6 degrees C showed a significantly higher cure rate when administered 400 mg/day compared with 300 mg/day . 2) No significant difference between the groups was observed with respect to the improvement of quality of life (QOL), assessed using a VAS . In patients with a temperature > or = 38.6 degrees C, however, significantly higher improvement rates were demonstrated on days 3, 5 and 6 of treatment at 400 mg/day compared with 300 mg/day . 3) The reconsultation rate was significantly lower in the group administered 400 mg/day compared with the group administered 300 mg/day . No significant difference between the groups was observed in patients with a temperature < or = 38.5 degrees C . However, in the patients with a temperature > or = 38.6 degrees C, treatment at 400 mg/day achieved a significantly lower reconsultation rate compared with 300 mg/day . 4) Nonsteroidal anti-inflammatory drugs (NSAIDs) were concomitantly administered to 64.3% of the patients, but no significant difference in the cure rate was observed between patients with or without concomitant use of NSAIDs . 5) Among all of the patients, 12.7% were positive for the influenza virus, and anti-influenza drugs were concomitantly administered to 41.3% of them . However, no significant difference in the cure rate was observed between the group administered levofloxacin alone and the group concomitantly administered anti-influenza drugs . 6) The incidence of adverse drug reactions was 0.84% in the group administered 400 mg/day and 0.50% in the group administered 300 mg/day . No significant difference was observed between these groups and no serious adverse drug reactions occurred . In conclusion, for treating patients with acute upper respiratory tract infection accompanied by fever (> or = 38.6 degrees C) and suspected bacterial infection, levofloxacin dosage of 400 mg/day (divided into 2 doses) was superior to 300 mg/day (divided into 3 doses) in terms of therapeutic effect, QOL, and the reconsultation rate . This was considered to be an administration method worth recommending, including its safety . In patients with a temperature of 38.0 degrees C to 38.5 degrees C, administration of levofloxacin at 300 mg/day was confirmed to demonstrate a sufficient therapeutic effect.

Jpn J Antibiot, 2003 Dec, 56(6), 674 - 80
{Comparative antibacterial activity of carbapenems against P . aeruginosa (2)}; Hikida M et al.; Susceptibility testing of 288 clinical isolates of P . aeruginosa in 2000 was performed by the disk diffusion method with observation at regular time course . Detailed analysis of the shape of the zones of inhibition gave interesting results, i.e . double zone of inhibition was found in MEPM specifically, unlike BIPM and IPM . The incidence was 50% . Moreover same phenomenon was detected in CAZ . After analyzing this phenomenon from the results of short-time-killing curve and inducibility of AmpC beta-lactamase it seems that there is a close relationship between formation of double zone of inhibition and bactericidal activity in sub-MIC drug concentration.

J Allergy Clin Immunol, 2004 Mar, 113(3), 519 - 27
Drug interaction with T-cell receptors: T-cell receptor density determines degree of cross-reactivity; Depta JP et al.; BACKGROUND: Immune-mediated adverse reactions to drugs are often due to T-cell reactivity, and cross-reactivity is an important problem in pharmacotherapy . OBJECTIVE: We investigated whether chemical inert drugs can stimulate T cells through their T-cell receptor (TCR) and analyzed the cross-reactivities to related compounds . METHODS: We transfected human TCRs isolated from two drug-reactive T-cell clones (TCCs) by PCR into a TCR-negative mouse T-cell hybridoma . The TCCs were isolated from a patient with drug hypersensitivity to the antibacterial sulfonamide sulfamethoxazole (SMX) . RESULTS: The transfectants reacted to SMX only in the presence of antigen-presenting cells (APCs) . Glutaraldehyde-fixed APCs, however, were sufficient to elicit T-cell stimulation, indicating a processing-independent direct interaction of the drug with the TCR and MHC molecule . The transfected hybridomas secreted IL-2 in a drug dose-dependent manner, whereas the degree of reactivity was dependent on the level of TCR expression . One transfectant reacted not only to SMX but also to related sulfonamide compounds . Interestingly, high TCR expression increased cross-reactivity to other structurally related compounds . In addition, SMX-specific TCR cross-reacted only with sulfonamides bearing a sulfanilamide core structure but not with sulfonamides such as celecoxib, furosemide, or glibenclamide . CONCLUSIONS: These results demonstrate that the T-cell reactivity to drugs is solely determined by the TCR . Moreover, these results show that cross-reactivity of structurally similar compounds correlates with the density of the TCR . Stably transfected T-cell hybridomas may represent a powerful screening tool for cross-reactivity of newly generated sulfonamide-containing compounds such as celecoxib.

Bioorg Med Chem Lett, 2004 Mar 22, 14(6), 1427 - 31
Design and synthesis of indolo{2,3-a}quinolizin-7-one inhibitors of the ZipA-FtsZ interaction; Jennings LD et al.; The binding of FtsZ to ZipA is a potential target for antibacterial therapy . Based on a small molecule inhibitor of the ZipA-FtsZ interaction, a parallel synthesis of small molecules was initiated which targeted a key region of ZipA involved in FtsZ binding . The X-ray crystal structure of one of these molecules complexed with ZipA was solved . The structure revealed an unexpected binding mode, facilitated by desolvation of a loosely bound surface water.

Bioorg Med Chem Lett, 2004 Mar 22, 14(6), 1423 - 6
The discovery of biaryl acids and amides exhibiting antibacterial activity against Gram-positive bacteria; Look GC et al.; Solid-phase synthetic methods for biaryl-based compounds were developed resulting in the construction of two 1000-member libraries . Numerous compounds were identified by high-throughput screening using whole cell screens to exhibit anti-microbial activity against Gram-positive bacteria . A series of biaryl compounds containing natural and unnatural amino acids were made to explore the SAR of the amino acid functionality.

Clin Pharmacokinet, 2004, 43(4), 239 - 52
Clinical pharmacokinetics of quinupristin/dalfopristin; Bearden DT; Quinupristin/dalfopristin is a streptogramin antibacterial with a wide spectrum of Gram-positive antibacterial activity . The drug has minimal oral absorption and is administered intravenously as a fixed 30 : 70 ratio of quinupristin to dalfopristin . A linear relationship has been observed between the dose administered and maximum plasma concentrations . Single-dose administration of 7.5 mg/kg produced a maximal plasma concentration of 2.3-2.7 mg/L for quinupristin and 6.1-8.2 mg/L for dalfopristin . The area under the concentration-time curve (AUC) obtained with the same dose was 2.7-3.3 and 6.5-7.7 mg . h/L for quinupristin and dalfopristin, respectively . Repeated administration results in 13-21% increases in maximum plasma concentrations and 21-26% increases in AUC for both quinupristin and dalfopristin . Quinupristin and dalfopristin exhibit steady-state volumes of distribution of 0.46-0.54 and 0.24-0.30 L/kg, respectively . Quinupristin exhibits higher protein binding (55-78%) than dalfopristin (11-26%), though both entities distribute well into tissues . Concentrations exceeding those in blood have been reported for the kidney, liver, spleen, salivary glands and white blood cells of primates . Extravascular penetration, as measured in blister fluid, is 40-80% . Both quinupristin and dalfopristin are extensively metabolised via nonenzymatic reactions . Quinupristin is conjugated to form two active compounds, a cysteine moiety and a glutathione moiety . Dalfopristin is hydrolysed to the active metabolite pristinamycin IIA . The metabolites exert antibacterial activity similar to that of the parent compounds . Quinupristin/dalfopristin is excreted primarily in the faeces (75-77%), with lesser renal excretion (15-19%) . The elimination half-lives of quinupristin and dalfopristin are similar, and are 0.7-1.3 hours after single doses . The metabolites have slightly longer half-lives, ranging from 1.2 to 1.8 hours . With repeated doses, plasma clearance of quinupristin and dalfopristin is reduced by approximately 20% compared with single doses, resulting in clearances of 0.7-0.8 L/h/kg . Saturable protein binding has been hypothesised as a causative mechanism . Quinupristin/dalfopristin is an inhibitor of cytochrome P450 3A4, resulting in multiple drug interactions . Ciclosporin AUC increased by 5-222% when coadministered with quinupristin/dalfopristin . Careful monitoring of patients receiving drugs that are substrates of cytochrome P450 3A4 is suggested.Quinupristin/dalfopristin is administered at 7.5 mg/kg every 8-12 hours, depending upon the severity of infection . The pharmacodynamic parameter linked with antibacterial activity for quinupristin/dalfopristin appears to be the ratio of AUC to the minimal inhibitory concentration . The additional activity of a prolonged post-antibiotic effect may also be important for efficacy.

J Immunol, 2004 Mar 15, 172(6), 3620 - 7
B cells are crucial for both development and maintenance of the splenic marginal zone; Nolte MA et al.; The splenic marginal zone is a unique compartment that separates the lymphoid white pulp from the surrounding red pulp . Due to the orchestration of specialized macrophages and B cells flanking a marginal sinus, this compartment plays an important role in uptake of blood-borne Ags and it gives the spleen its specialized function in antibacterial immunity . In this study, we demonstrate that both development and maintenance of this marginal zone is highly dependent on the presence of B cells . Spleens from B cell-deficient mice were found to lack both metallophilic and marginal zone macrophages as well as mucosal addressin cellular adhesion molecule-1+ sinus lining cells . Using an inducible Cre/loxP-driven mouse model in which mature B cells could be partially depleted by removal of the B cell receptor subunit Igalpha, we could show that the integrity and function of an established marginal zone was also dependent on the presence of B cells . This was confirmed in a transgenic model in which all B cells were gradually depleted due to overexpression of the TNF family member CD70 . The loss of all cellular subsets from the marginal zone in these CD70 transgenic mice was effectively prevented by crossing these mice on a CD27(-/-) or TCRalpha(-/-) background, because this prohibited the ongoing B cell depletion . Therefore, we conclude that B cells are not only important for the development, but also for maintenance, of the marginal zone . This direct correlation between circulating B cells and the function of the spleen implies an increased risk for B cell lymphopenic patients with bacterial infections.

Aquat Toxicol, 2004 Apr 14, 67(2), 167 - 79
Effects of triclosan on the early life stages and reproduction of medaka Oryzias latipes and induction of hepatic vitellogenin; Ishibashi H et al.; Triclosan (2,4,4'-trichloro-2'-hydroxydiphenyl ether) is widely used as antibacterial agent in various industrial products, such as textile goods, soap, shampoo, liquid toothpaste and cosmetics, and often detected in wastewater effluent . In this study, the effects of TCS on the early life stages and reproduction of medaka (Oryzias latipes) were investigated . The 96-h median lethal concentration value of TCS for 24-h-old larvae was 602 microg/l . The hatchability and time to hatching in fertilized eggs exposed to 313 microg/l TCS for 14 days were significantly decreased and delayed, respectively . An assessment of the effects of a TCS 21-day exposure period on the reproduction of paired medaka showed no significant differences in the number of eggs produced and fertility among the control and 20, 100 and 200 microg/l TCS treatment groups . However, concentrations of hepatic vitellogenin were increased significantly in males treated with TCS at 20 and 100 microg/l . In the F(1) generations, although the hatching of embryos in the 20 microg/l treatment showed adverse effects, there was no dose-response relationship between hatchability and TCS treatment levels . These results suggest that TCS has high toxicity on the early life stages of medaka, and that the metabolite of TCS may be a weak estrogenic compound with the potential to induce vitellogenin in male medaka but with no adverse effect on reproductive success and offspring.

J Comb Chem, 2004 Mar-Apr, 6(2), 230 - 8
Tetrahydrofuran-based amino acids as library scaffolds; Edwards AA et al.; A furanose sugar amino acid (SAA) has been utilized as a library scaffold for the first time . Two furanose SAA scaffolds were examined to illustrate their potential for derivatization . The resulting 99-member library contained three orthogonal points of diversification that allowed easy access to ethers and carbamates from a hydroxyl moiety, a range of ureas from an azide (via an amine), and a range of amides from a methyl ester . The novel amide formation (by displacement of the methoxide from the methyl ester moiety) was achieved in good yield and purity with high structural confidence . Full characterization of several library intermediates (including a crystal structure) was obtained . The library was submitted for antibacterial screening.

J Dent, 2004 Mar, 32(3), 247 - 54
The effect of light-curing modes on the microleakage of cervical resin composite restorations; Kubo S et al.; OBJECTIVE: This study investigated the effect of light-curing modes on the microleakage of cervical resin composite restorations . METHODS: Eighty wedge-shaped cervical cavities, C-factor approximately 1.3, were prepared on the labial surface of bovine incisors . The cavities were treated with a two-step experimental self-etching primer adhesive system containing an antibacterial monomer (ABF), according to the manufacturer's instructions, and filled with a single increment of a hybrid resin composite . The restorations were allocated randomly into four groups of 20: Group 1-the restorations were light-cured for 40 s with a conventional light-curing unit (New Light VL-II); Group 2-the restorations were cured with Candelux using a two-step mode; Group 3-the restorations were cured with Astralis 7 using a ramping mode; Group 4-the restorations were light-cured for 3 s with a plasma arc light-curing unit (Wave Light) . Half of the specimens from each group were subjected to thermocycling (5-60 degrees C, 15 s dwell time, 5000 cycles) prior to immersion in 0.5% basic fuchsin . The teeth were sectioned and the degrees of dye penetration were scored . The data were analyzed with either the Kruskal-Wallis test or the Mann-Whitney U-test (p < 0.05) RESULTS: No significant differences were found in the microleakage scores among the light-curing modes used . The restorations tended to display more microleakage when they were subjected to thermocycling, but the differences were not statistically significant . CONCLUSIONS: These findings suggest that light-curing modes may have no effect on the microleakage of cervical cavities with a small C-factor, as is the case in this study.

Clin Infect Dis, 2004 Mar 15, 38(6), 864 - 70 Epub 2004 Mar 01.
Clinical relevance of bacteriostatic versus bactericidal mechanisms of action in the treatment of Gram-positive bacterial infections; Pankey GA et al.; The distinction between bactericidal and bacteriostatic agents appears to be clear according to the in vitro definition, but this only applies under strict laboratory conditions and is inconsistent for a particular agent against all bacteria . The distinction is more arbitrary when agents are categorized in clinical situations . The supposed superiority of bactericidal agents over bacteriostatic agents is of little relevance when treating the vast majority of infections with gram-positive bacteria, particularly in patients with uncomplicated infections and noncompromised immune systems . Bacteriostatic agents (e.g., chloramphenicol, clindamycin, and linezolid) have been effectively used for treatment of endocarditis, meningitis, and osteomyelitis--indications that are often considered to require bactericidal activity . Although bacteriostatic/bactericidal data may provide valuable information on the potential action of antibacterial agents in vitro, it is necessary to combine this information with pharmacokinetic and pharmacodynamic data to provide more meaningful prediction of efficacy in vivo . The ultimate guide to treatment of any infection must be clinical outcome.

Prostate Cancer Prostatic Dis, 2004, 7(1), 21 - 31
The Janus-faced nature of prostasomes: their pluripotency favours the normal reproductive process and malignant prostate growth; Ronquist G et al.; Prostasomes are submicron secretory granules synthesized, stored and secreted by the epithelial cells of the human prostate gland . They are membrane-surrounded also in their extracellular appearance and the membrane architecture is composite . They are believed to be life-giving and act as protectors of the spermatozoa in the lower and upper female genital tract on their way to the ovum . Hence, the prostasomes are immunosuppressive and inhibitory of complement activation . Further, they promote sperm's forward motility and have antioxidant and antibacterial capacities . The prostasomes with their many composite abilities seem to turn against the host cell after the age of 50 y being conducive to the transition of the normal prostate epithelial cell into a neoplastic cell and therewith lay the foundations of the very high prevalence of prostate cancer of men of more than 50 y of age.

J Biochem (Tokyo), 2004 Jan, 135(1), 65 - 70
Antibacterial activity of peptides derived from the C-terminal region of a hemolytic lectin, CEL-III, from the marine invertebrate Cucumaria echinata; Hatakeyama T et al.; Several synthetic peptides derived from the C-terminal domain sequence of a hemolytic lectin, CEL-III, were examined as to their action on bacteria and artificial lipid membranes . Peptide P332 (KGVIFAKASVSVKVTASLSK-NH(2)), corresponding to the sequence from residue 332, exhibited strong antibacterial activity toward Gram-positive bacteria . Replacement of each Lys in P332 by Ala markedly decreased the activity . However, when all Lys were replaced by Arg, the antibacterial activity increased, indicating the importance of positively charged residues at these positions . Replacement of Val by Leu also led to higher antibacterial activity, especially toward Gram-negative bacteria . The antibacterial activity of these peptides was correlated with their membrane-permeabilizing activity toward the bacterial inner membrane and artificial lipid vesicles, indicating that the antibacterial action is due to perturbation of bacterial cell membranes, leading to enhancement of their permeability . These results also suggest that the hydrophobic region of CEL-III, from which P332 and its analogs were derived, may play some role in the interaction with target cell membranes to trigger hemolysis.

Environ Sci Technol, 2004 Feb 15, 38(4), 1148 - 53
Pollution-induced community tolerance of soil microbial communities caused by the antibiotic sulfachloropyridazine; Schmitt H et al.; Little is known about the environmental hazards linked to the treatment of farm animals with antibiotics and subsequent spreading of manure, especially regarding soil microbial communities . In this investigation, pollution-induced community tolerance (PICT) of bacteria from soils artificially spiked with the sulfonamide sulfachloropyridazine (SCP) was investigated . Tolerance of the bacterial communities after 3 weeks' exposure to SCP was determined by analyzing the sensitivity of 31 microbial metabolic processes in microtiter plates . Bacterial suspensions extracted from soils containing higher concentrations of SCP showed an increased tolerance of their metabolic activities to this antibiotic . An increase in tolerance by 10% was found at 7.3 mg/kg dw SCP . The PICT effect could be demonstrated by both a shift in the tolerance of the average of all metabolic activities and a shift of the physiological process sensitivity distributions made up from the single metabolic processes . The PICT effect was accompanied by smaller changes in the community-level physiological profile (CLPP) . To conclude, PICT has been shown to be a versatile and illustrative method for the detection of the effects of antibacterial agents on soil microorganisms.

Ann Intern Med, 2004 Mar 2, 140(5), 321 - 9
Effect of antibacterial home cleaning and handwashing products on infectious disease symptoms: a randomized, double-blind trial; Larson EL et al.; BACKGROUND: Despite the widespread household use of cleaning and personal hygiene products containing antibacterial ingredients, their effects on the incidence of infectious disease symptoms have not been studied . OBJECTIVE: To evaluate the effect of antibacterial cleaning and handwashing products for consumers on the occurrence of infectious disease symptoms in households . DESIGN: Randomized, double-blind clinical trial . SETTING: Northern Manhattan inner-city neighborhood, New York . PARTICIPANTS: 238 primarily Hispanic households (1178 persons) that included at least one preschool-age child . Interventions: Households were randomly assigned to use either antibacterial or nonantibacterial products for general cleaning, laundry, and handwashing . All products were commercially available, but the packaging was blinded and the products were provided free to participants . MEASUREMENTS: Hygiene practices and infectious disease symptoms were monitored by weekly telephone calls, monthly home visits, and quarterly interviews for 48 weeks . RESULTS: Symptoms were primarily respiratory: During 26.2% (717 of 2736) of household-months, 23.3% (640 of 2737) of household-months, and 10.2% (278 of 2737) of household-months, one or more members of the household had a runny nose, cough, or sore throat, respectively . Fever was present during 11% (301 of 2737) of household-months, vomiting was present in 2.2% (61 of 2737), diarrhea was present in 2.5% (69 of 2737), and boils or conjunctivitis were present in 0.77% (21 of 2737) . Differences between intervention and control groups were not significant for any symptoms (all unadjusted and adjusted relative risks included 1.0) or for numbers of symptoms (overall incidence density ratio, 0.96 {95% CI, 0.82 to 1.12}) . CONCLUSIONS: The tested antibacterial products did not reduce the risk for symptoms of viral infectious diseases in households that included essentially healthy persons . This does not preclude the potential contribution of these products to reducing symptoms of bacterial diseases in the home.

Clin Ther, 2004 Jan, 26(1), 48 - 62
Efficacy and tolerability of once-daily oral telithromycin compared with clarithromycin for the treatment of community-acquired pneumonia in adults; Mathers Dunbar L et al.; BACKGROUND: Telithromycin is a new antibacterial agent of the ketolide class designed to provide optimal treatment against common bacterial respiratory tract pathogens . Telithromycin was derived by structural modification of the basic macrolide molecule to allow tight binding to the bacterial ribosome that enhances potency and minimizes the risk for the development of resistant strains . OBJECTIVE: The aim of this study was to compare the efficacy and tolerability of telithromycin 800 mg once daily with those of high-dose clarithromycin (500 mg twice daily), each for 10 days, in the treatment of adult patients with community-acquired pneumonia (CAP) . METHODS: This randomized, double-blind, double-dummy, parallel-group clinical trial was conducted at 54 centers in the United States, Canada, Argentina, and Chile . Patients aged >or=18 years with acute CAP were randomized to receive 10-day treatment with oral telithromycin 800 mg once daily (administered as two 400-mg encapsulated tablets in the morning) and placebo (administered as 2 encapsulated tablets identical to the telithromycin in the evening) or high-dose clarithromycin (500 mg administered as two 250-mg identical encapsulated tablets twice daily) . The primary outcome measure was clinical outcome at the posttherapy, test-of-cure visit (days 17-24 after the completion of therapy) in the clinically assessable per-protocol population . Secondary efficacy variables included bacteriologic outcome at the posttherapy, test-of-cure visit, and clinical and bacteriologic outcomes at the late posttherapy visit (day 31-45) . Tolerability was assessed using investigator observation, patient self-reporting, clinical laboratory data, a 12-lead electrocardiogram, and physical examination (including vital signs) . RESULTS: A total of 493 patients were enrolled and 448 patients received >or=1 dose of study medication (224 patients/group) . A diagnosis of CAP was confirmed in 416 patients (205 men, 211 women; median age, 43 years; telithromycin, n = 204; clarithromycin, n = 212) . Clinical cure rates were 88.3% (143/162) in the telithromycin group and 88.5% ( 138/56) in the clarithromycin group . Bacterial eradication rates were comparable between treatment groups (telithromycin, (28/32) {87.5%}; clarithromycin, (29/30) {96.7%} . Both treatment were fairly well tolerated; adverse events were experienced in 57.0% of the patients treated with telithromycin and 49.1% of those treated with clarithromycin; most of these were assessed as mild . CONCLUSIONS: In this study of adult patients with CAP, telithromycin 800 mg once daily was an effective and fairly well-tolerated regimen for initial empiric treatment, with clinical and bacteriologic efficacy and tolerability equivalent to therapy with high-dose clarithromycin (500 mg twice daily).

Ann Pharmacother, 2004 Apr, 38(4), 634 - 40 Epub 2004 Feb 27.
Nitazoxanide treatment for giardiasis and cryptosporidiosis in children; Bailey JM et al.; OBJECTIVE: To review the pharmacology, pharmacokinetics, adverse effects, drug interactions, dosing recommendations, and clinical efficacy of nitazoxanide, a new antiprotozoal/anthelmintic/antibacterial agent . DATA SOURCES: A MEDLINE search (1966-February 2004) of both human and animal research data published in the English language was conducted . STUDY SELECTION AND DATA EXTRACTION: All primary and review articles pertaining to the MEDLINE search were reviewed for inclusion . Emphasis was placed on randomized, double-blind, placebo-controlled trials . DATA SYNTHESIS: Nitazoxanide is approved for the treatment of giardiasis and cryptosporidiosis (first drug approved for the latter indication) in immune-competent children <12 years of age . Most studies in immune-competent patients have reported clinical and parasitologic response rates close to 80% and 70%, respectively, for both indications . Response rates have been lower in immune-compromised patients . CONCLUSIONS: Nitazoxanide should be available for patients unable to tolerate or adhere to first-line therapy employed for these intestinal protozoa.

Respirology, 2004 Mar, 9(S1), S56 - S59
Appendix II: How to use antibacterial agents in the elderly; Assessment of the efficacy of antibacterial agents; Assessment of the efficacy of antibacterial agents The committee for The Japanese Respiratory Society guidelines in management of respiratory infections . Respirology 2004; 9: S40-S42

Respirology, 2004 Mar, 9(S1), S16 - S24
Antibacterial therapy of hospital-acquired pneumonia; Novel antibacterial agents for skin and skin structure infections; Department of Dermatology, St . Luke's-Roosevelt Hospital Center, 1090 Amsterdam Avenue, New York, NY 10025, USAWith the continuing development of clinical drug resistance among bacteria and the advent of resistance to the recently released agents quinupristin-dalfopristin and linezolid, the need for new, effective agents to treat multidrug-resistant gram-positive infections remains important . With treatment options limited, it has become critical to identify antibiotics with novel mechanisms of activity . Several new drugs have emerged as possible therapeutic alternatives . This review focuses on agents newly introduced and those presently in clinical development for the treatment of skin and skin structure infections . Linezolid, quinupristin-dalfopristin, and daptomycin have been approved by the Food and Drug Administration for the treatment of skin and skin structure infections . Two newer compounds, oritavancin and dalbavancin, are in clinical development for this indication . In addition, the quinolones moxifloxacin and gatifloxacin recently were approved for cutaneous infections . Learning objective: At the conclusion of this learning activity, participants should be familiar with the modes of action, clinical indications, dosage regimens, and contraindications and cautions for several novel antibacterial agents for skin and skin structure infections.

Transpl Infect Dis, 2003 Dec, 5(4), 167 - 73
Infectious complications in patients randomized to receive allogeneic bone marrow or peripheral blood transplantation; Nucci M et al.; Very few data are available on the comparison of infectious complications in peripheral blood stem cell transplantation (PBSCT) and bone marrow transplant (BMT) . The objective of this study was to evaluate the severity and frequency of infectious complications in patients randomized to receive PBSCT or BMT . We retrospectively reviewed the charts of all patients included in a randomized clinical trial comparing PBSCT (27 patients) and BMT (29 patients) . We analyzed two periods: pre-engraftment and post-engraftment . In the pre-engraftment period, we compared the two groups with respect to the duration of neutropenia, antibiotic use and hospitalization, and documentation of infection . In the post-engraftment period, we analyzed the occurrence and severity of graft-versus-host disease (GVHD), duration of cyclosporine, corticosteroids, antibiotic, antiviral and antifungal prophylaxis, number of episodes of infection, and death rates . Patients receiving PBSCT had shorter duration of neutropenia, but there were no differences in the incidence of infections or duration of antibiotic therapy . Patients receiving PBSCT had a higher incidence of extensive chronic GVHD (65% vs . 39%, P=0.08), longer duration of cyclosporine use (risk ratio {RR} 1.97), corticosteroids (RR 1.66), antibacterial (RR 2.60), antifungal (RR 2.50), anti-Pneumocystis carinii (RR 2.06) and anti-cytomegalovirus (RR 1.44) prophylaxis, and more infectious episodes (3.65 vs . 2.32 per 1000 days at risk, RR 1.57) . There were no differences in death rates . Multivariate analysis identified the use of steroids as the most significant variable associated with infectious episodes . PBSCT was associated with more infections in the post-engraftment period.

J Fish Dis, 2004 Jan, 27(1), 57 - 64
A synthetic antibacterial peptide from Mytilus galloprovincialis reduces mortality due to white spot syndrome virus in palaemonid shrimp; Dupuy JW et al.; White spot syndrome virus (WSSV) isolated from Penaeus monodon was found to be highly infective for the western Mediterranean shrimp, Palaemon sp . Using polymerase chain reaction (PCR), it was demonstrated that such shrimp are not naturally carriers of WSSV . Following challenge with virus, mortality reached 100% 3.5-4 days after injection at 22 degrees C . Incubation of infected shrimp at 10 degrees C totally suppressed the mortality which rapidly developed when shrimp were returned to 18 or 22 degrees C . Preincubation of WSSV with mature synthetic mytilin significantly reduced shrimp mortality with a 50% efficient dose of about 5 microM . Survival of shrimp was not due to the development of an active mechanism of defence as re-injection of WSSV produced the same mortality pattern . Mortality was probably due to WSSV replication as dot blot failed to detect viral DNA in the injection sample but was positive 1 day post-injection . Protection by mytilin was by interaction at the virus level, preventing replication as no WSSV nucleic acid was detected by PCR even after 7 days in shrimp injected with WSSV preincubated with 10 or 50 microM mytilin.

Antimicrob Agents Chemother, 2004 Mar, 48(3), 946 - 53
Activities of ciprofloxacin and moxifloxacin against Stenotrophomonas maltophilia and emergence of resistant mutants in an in vitro pharmacokinetic-pharmacodynamic model; Ba BB et al.; A two-compartment in vitro pharmacokinetic-pharmacodynamic model, with full computer-controlled devices, was used to accurately simulate human plasma pharmacokinetic profiles after multidose oral regimens of ciprofloxacin (750 mg every 12 h) and moxifloxacin (400 mg every 24 h) during 48 h . Pharmacodynamics of these drugs was investigated against three quinolone-susceptible strains of Stenotrophomonas maltophilia (MICs of ciprofloxacin and moxifloxacin of 0.5 to 2 and 0.0625 to 0.5 microg/ml, respectively) . The first dose of ciprofloxacin and moxifloxacin reduced the bacterial count by 1 and 2 log CFU/ml, respectively, prior to a bacterial regrowth that reached the plateau value of the growth control curve at 13 to 24 h versus 24 to 36 h and persisted despite repeated administration of both drugs . The surviving bacterial cells were quinolone-resistant mutants (2 to 128 times the MIC) that exhibited cross-resistance to unrelated antibiotics . Their antibiotic resistance probably resulted from the overproduction of different multidrug resistance efflux system(s) . C(max)/MIC and area under the concentration-time curve from 0 to 24 h (AUC(0-24))/MIC values were at least threefold higher for moxifloxacin than for ciprofloxacin . Moreover, integral parameters of ciprofloxacin and moxifloxacin, in particular the area under the killing and regrowth curve from 0 to 48 h (AUBC(0-48), 342.3 to 401.3 versus 295.2 to 378.7 h x log CFU/ml, respectively) and the area between the control growth curve and the killing and regrowth curve from 0 to 48 h (ABBC(0-48), 40.4 to 101.1 versus 72.9 to 144.7 h x log CFU/ml, respectively), demonstrated a better antibacterial effect of moxifloxacin than ciprofloxacin on S . maltophilia . However, selection of resistant mutants by both fluoroquinolones, although delayed with moxifloxacin, emphasizes the need to use maximal dosages and combined therapy in the treatment of systemic S . maltophilia infections.

Anticancer Res, 2003 Nov-Dec, 23(6D), 5165 - 71
Colorectal adenomas produce lysozyme; Rubio CA; Lysozyme is an innate non-immunologic antibacterial enzyme produced by the Paneth cells of the upper intestinal tract . Lysozyme is not normally secreted in the lower intestinal tract . Previous reports indicate, however, that lysozyme may be secreted by colorectal neoplasias . The aim was to audit lysozyme expression in colorectal diseases including neoplasias . For that purpose, sections were stained with lysozyme (Muramidase), Ki67 (MIB1) and CD 68 . Intense lysozyme overexpression (+++) was compared among 177 colorectal tissues: 35 having normal mucosa, 20 regenerative mucosa in inflammatory bowel disease (IBD), 2 inflammatory polyps, 3 collagenous colitis, 2 melanosis coli, 21 hyperplastic polyps, 42 tubular adenomas, 9 serrated adenomas, 30 villous adenomas and 13 invasive carcinomas . Intense lysozyme overexpression (+++) was found in 9.5% of the hyperplastic polyps, in 97.6% of the tubular adenomas, in 88.9% of the serrated adenomas, in 93.3% of the villous adenomas, in 76.9% of the carcinomas, but in none of the other tissues investigated . Neoplastic colorectal cells may acquire the capacity to produce lysozyme . The presence of that enzyme may not be a haphazard, capricious event in mutated colorectal epithelial cells but part of a more elaborate molecular behavior, not necessarily antibacterial . Recently, it was demonstrated that patients having lysozyme-secreting breast carcinomas were associated with a favorable prognosis . Whether lysozyme expression has any bearing on the biological behavior of colorectal carcinomas remains to be elucidated . Lysozyme overexpression (+++) also occurred in 2 of the 21 hyperplastic polyps, suggesting that intense lysozyme production might herald a possible dysplastic evolution in some hyperplastic polyps.

Am J Obstet Gynecol, 2004 Feb, 190(2), 448 - 55
Labor induces a maternal inflammatory response syndrome; Molloy EJ et al.; OBJECTIVE: We studied the effect of labor on maternal neutrophil phenotype . STUDY DESIGN: Neutrophil apoptosis with inflammatory cytokines and the expression of CD11b, CD34 and toll-like receptor 4 (TLR4) were assessed with flow cytometry in women at uncomplicated vaginal delivery (VD), and elective cesarean section (ElCS) without labor, emergency cesarean section with (EmCSL+) or without (EmCSL-) labor . RESULTS: Spontaneous neutrophil apoptosis is delayed in maternal neutrophils after VD, EmCSL+ or EmCSL- versus ElCS . In all groups lipopolysaccharide delayed apoptosis and increased CD11b expression . Elevated TLR4 expression in ElCS was associated with lipopolysaccharide responsiveness . CD34 was diminished in VD, indicating increased cell maturity . CONCLUSION: Normal labor primes the neutrophil and may enhance antibacterial function by inducing a mild maternal inflammatory response syndrome . Delayed neutrophil apoptosis may promote the neutrophilia seen in women after VD . We suggest that labor of any duration may be immunologically beneficial to the parturient.

Bioorg Med Chem Lett, 2004 Mar 8, 14(5), 1273 - 7
Syntheses and biological evaluation of new fluoroquinolone antibacterials containing chiral oxiimino pyrrolidine; Choi DR et al.; The design and syntheses of new fluoroquinolone antibacterial agents having pyrrolidine ring at C-7 position are described . The pyrrolidine ring is optically active and possesses methyloxime functional group . Two of them have excellent in vitro antibacterial activities and pharmacokinetic profiles.

Bioorg Med Chem Lett, 2004 Mar 8, 14(5), 1259 - 63
DNA binding ligands targeting drug-resistant Gram-positive bacteria . Part 2: C-terminal benzimidazoles and derivatives; Burli RW et al.; The synthesis and in vitro potency of DNA minor-groove binding antibacterials lacking the C-terminal amide bond are described . The crescent shaped molecules bear the positively charged amino group at an internal pyrrole unit instead of the C-terminus . Three structural parameters were investigated: the N-terminal unit, the internal amino group, and the C-terminal ring system . Several compounds demonstrated good in vitro potency against various Gram-positive bacteria and some molecules were moderately active against Escherichia coli, a representative Gram-negative strain.

Bioorg Med Chem Lett, 2004 Mar 8, 14(5), 1085 - 7
Synthesis of stavudine amino acid ester prodrugs with broad-spectrum chemotherapeutic properties for the effective treatment of HIV/AIDS; Sriram D et al.; A series of prodrugs of stavudine were synthesized in an effort to enhance spectrum of chemotherapeutic properties for the effective treatment of HIV/AIDS . The 5'-OH function of stavudine was esterified with ciprofloxacin, norfloxacin, isoniazide, pyrazinamide, piperazine and dimethylamine acetic acid . The anti-HIV-1 activity of the esters was determined in CEM cell line and stavudine ester bearing piperazine acetic acid was found to be the most potent compound with a selective index of >15,723 . Stavudine prodrug bearing ciprofloxacin and norfloxacin acetic acid showed 100% inhibition against Mycobacterium tuberculosis H(37)Rv at 6.25 microg/mL . The prodrugs also exhibited antibacterial activity against 24 pathogenic bacteria . In vitro hydrolysis of the various esters in human plasma indicated that these agents were relatively stable toward plasma esterases with t(1/2) ranging from 20-240 min.

Am J Clin Dermatol, 2004, 5(1), 17 - 29
Disorders of keratinization: diagnosis and management; Shwayder T; Disorders of cornification are a group of diseases that share abnormalities in the manufacture or desquamation of corneocytes . This paper reviews the major and a few of the rarer ones with a concentration on their therapy . Ichthyosis vulgaris is probably a post-translational defect in pro-filaggrin expression . It shows fine white flaky scales of the extensor surfaces, trunk, flank, lower legs but spares the folds and wet areas . Treatment is with aggressive moisturization . Hydrocortisone creams may be needed to control itch . Recessive X-linked ichthyosis is due to a deficiency of cholesterol sulfatase . Boys with this condition show small dark scales around the ears, sides of the neck, extensor surfaces of the arms and legs, and the peri-umbilical region . It spares the folds and face . Treatment is with moisturizers, topical retinoid creams or with topical cholesterol-based creams . Checking for signs of contiguous gene disorders (Kallman or Conradi-Hunermann syndromes) is necessary . Bullous congenital ichthyosiform erythroderma is caused by mutations in keratins 1 and/or 10 . These patients are born as bright red babies with large blisters and erosions . Slowly, a porcupine quill-like waxy scaling develops . Blistering continues throughout life . Secondary infections of the skin cause pain, debility, and a very foul odor . Treatment is difficult . Topical moisturizers, descalers and retinoid creams help a little . Oral retinoids help a lot but can cause increased blistering . Controlling the odor is an ongoing issue using antibacterial washes, absorbing powders, and masking fragrances . Autosomal recessive ichthyosis is a term for both lamellar ichthyosis and congenital ishthysosiform erythroderma . They are caused by various mutations in transglutaminase-1 gene . In both instances patients are born as 'collodion babies' . Lamella ichthyosis has the very recognizable plate-like scale over the entire body . Children with congenital ishthysosiform erythroderma are red all over with a finer scale in some places and plate-like scales in others . Treatment is with topical moisturizers, retinoid creams, descalers, and in some cases oral retinoids . Palmar plantar keratodermas occur in conjunction with some ichthyoses, but also by themselves . Some are diffuse and others have discrete, corn-like hardenings . Treatment with topical acids, propylene glycol and retinoid creams help to some extent.Throughout the article pearls from my practice are included to assist the clinician in the day-to-day handling of these patients . A short section on genetic counseling concludes this article.

J Med Food, 2003 Winter, 6(4), 401 - 3
Antibacterial activity of Aristolochia bracteata root extracts; Negi PS et al.; Aristolochia bracteata (Aristolochiaceae) is used in traditional medicines as a gastric stimulant and in the treatment of cancer, lung inflammation, and dysentery and snake bites . The present investigation was undertaken to evaluate the antibacterial activity of Aristolochia bracteata root extracts . Roots of A . bracteata were powdered and successively extracted with ethyl acetate, acetone, methanol, and water for 8 hours each using a Soxhlet extractor . Antibacterial activity of dried extracts was evaluated by the pour-plate method against a few Gram-positive and Gram-negative bacteria . All the crude extracts showed a broad spectrum of antibacterial activity . The ethyl acetate extract was found to be the most effective . This study shows the potential for replacement of synthetic preservatives by the use of natural extracts.

J Endod, 2004 Feb, 30(2), 84 - 7
Antibacterial activity of 2% chlorhexidine gluconate and 5.25% sodium hypochlorite in infected root canal: in vivo study; Ercan E et al.; In this study, the antibacterial activity of the different antibacterial solutions using as root canal irrigant was compared in the teeth with pulpal necrosis and with periapical pathosis . Thirty root canals of incisors and premolars of 20 patients were used . Before and after the root canal preparation, two canal samples were obtained by a harvesting method using a sterile paper point in the first appointment . During the biomechanical preparation, both irrigant solutions were used for each tooth which were randomly divided into two groups . Last samples were also obtained before the root filling procedure . Samples obtained from the root canals were subjected to microbiologic processing, including anaerobic incubation on trypticase soy agar for 5 to 7 days . After counting of CFU on the plates, we concluded that both chlorhexidine gluconate and sodium hypochlorite were significantly effective to reduce the microorganisms in the teeth with necrotic pulp, periapical pathologies, or both, and could be used successfully as an irrigant solution.

Eur J Pharmacol, 2004 Feb 20, 486(2), 189 - 200
In vivo experimental approach for the risk assessment of fluoroquinolone antibacterial agents-induced long QT syndrome; Chiba K et al.; The proarrhythmic effects of fluoroquinolone antibacterial agents, sitafloxacin, gatifloxacin and moxifloxacin, were compared using three in vivo models . In the halothane-anesthetized dogs (n=5), intravenous 10-min infusion of gatifloxacin and moxifloxacin (1-3 mg/kg) prolonged the ventricular effective refractory period and the repolarization period to a similar extent, whereas sitafloxacin (1-3 mg/kg) prolonged the former only . No significant change was detected in other cardiovascular parameters . In the chronic complete atrioventricular block dogs (n=4), oral administration of 100 mg/kg of gatifloxacin (2 of 4) and moxifloxacin (3 of 4) induced torsades de pointes, which was not observed by sitafloxacin . In the alpha-chloralose-anesthetized rabbits (n=5), intravenous 20-min infusion of 60 mg/kg of gatifloxacin induced torsades de pointes (1 of 5) in the presence of methoxamine infusion, which was not observed by sitafloxacin or moxifloxacin . Thus, the halothane-anesthetized model is suitable for assessing QT prolongation, whereas the chronic complete atrioventricular block model is sensitive for detecting torsadogenic action of drugs . The alpha-chloralose-anesthetized model is the simplest and least expensive method, but its sensitivity to detect proarrhythmic action may be less great.

Crit Care, 2004 Feb, 8(1), R35 - 41 Epub 2003 Dec 23.
Endotoxin neutralization and anti-inflammatory effects of tobramycin and ceftazidime in porcine endotoxin shock; Goscinski G et al.; INTRODUCTION: Antibiotics used for treatment of severe bacterial infections have been shown to exert effects on the inflammatory response in addition to their antibacterial effects . The aim of the present study was to investigate whether the biological effects of endotoxin in a porcine model could be neutralized by tobramycin, and whether tobramycin or ceftazidime was able to modulate the inflammatory response . METHOD: Thirteen piglets were subjected to endotoxin infusion at an initial rate of 4 microgram/kg per hour, which was reduced to 1 microgram/kg per hour after 30 min . Before endotoxin infusion, the animals received saline (n = 4), ceftazidime (n = 5), or tobramycin (n = 4) at clinically relevant doses . Physiological parameters were measured and blood samples were taken hourly for 6 hours for analysis of tumour necrosis factor-alpha, IL-6 and endotoxin concentrations . RESULTS: All of the animals exhibited physiological signs of severe sepsis without major differences between the groups . Plasma endotoxin concentration was stable after 1 hour . There were no differences in endotoxin concentration or initial tumour necrosis factor-alpha and IL-6 concentrations between the groups . At 6 hours the IL-6 concentration was significantly lower in the ceftazidime group than in the saline group (P < 0.05), and in both the ceftazidime and the tobramycin groups there were significantly greater reductions from peak values (P < 0.05) . CONCLUSION: There was no neutralization of the biological effects of endotoxin in this porcine model . However, our data indicate a possible anti-inflammatory effect exerted by both ceftazidime and tobramycin, which manifested as a significantly greater reduction in IL-6 in comparison with the untreated group.

Clin Biochem, 2004 Mar, 37(3), 204 - 9
Circulating cytokines as markers of systemic inflammatory response in severe community-acquired pneumonia; Igonin AA et al.; OBJECTIVES: To assess the influence of empirical antibacterial therapy on systemic inflammatory response in patients with severe community-acquired pneumonia (CAP) . MATERIAL AND METHODS: Thirty consecutive patients with CAP meeting systemic inflammatory response syndrome (SIRS) criteria were recruited into this study . Blood samples for measurement of interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10) and C-reactive protein (CRP) concentrations were drawn on days 1, 3, 5, 7 and 10 . For analysis, these patients were divided into two subgroups according to British Thoracic Society (BTS) severity score and to clinical response to the initial antibacterial therapy . RESULTS: In the group with severe CAP (n= 15), serum concentrations of IL-6 (P = 0.0001), IL-8, (P = 0.001), IL-10 (P = 0.0001) and CRP (P = 0.0001) were significantly higher compared to patients from the non-severe group (n= 15) . IL-6 presented with a sharp decrease between days 1 and 3 in non-responders with severe CAP (P = 0.004) . IL-6 concentrations on day 1 were significantly associated with a response to empirical antibacterial treatment by day 3 . CONCLUSION: Despite the absence of a clinical response to empirical antibacterial treatment as assessed by conventional clinical parameters on day 3 in patients with severe CAP meeting SIRS criteria, there was a marked reduction in the degree of the systemic inflammatory response as reflected by IL-6 levels.

J Chromatogr A, 2004 Feb 20, 1027(1-2), 121 - 6
Capillary gas chromatography-mass spectrometry of volatile and semi-volatile compounds of Salvia officinalis; Radulescu V et al.; The essential oil and infusion of Salvia officinalis leaves have been widely applied in traditional medicine since ancient times and nowadays subjected to extensive research of their antibacterial, antiviral and cytotoxic properties . This paper shows chemical composition data of S . officinalis leaves essential oil isolated by steam distillation using a Clevenger-type apparatus . Also, the paper presents the chemical content of volatile and semi-volatile compounds of S . officinalis leaves infusion . The volatile and semi-volatile compounds of S . officinalis leaves infusion were isolated by solid-phase extraction (SPE) and liquid-liquid extraction with hexane and dichloromethane . SPE was carried out on 500 mg octadecylsilane (C18) cartridges and elution with dichloromethane . Liquid-liquid extraction was performed with hexane and dichloromethane . The essential oil in dichloromethane and infusion extracts in hexane and dichloromethane were analyzed by gas chromatography coupled with mass spectrometry . The quantitative results obtained by solid-phase extraction and liquid-liquid extraction showed that SPE on C18 performed the highest recovery of the volatile compounds from infusion sample.

Boll Chim Farm, 2003 Nov, 142(9), 406 - 9
Synthesis of some new thiazole derivatives of pharmaceutical interest; el-Ablack FZ; Reaction of 4-amino-3-phenyl-5-ethoxycarbonyl-thiazole-2-thione with phenylisothiocyanate gave (2) which when boiled with acetic acid gave (3) . Treatment of (2) with monochloroacetic acid resulted in the formation of thiazolidinone derivative (4) . Reaction of (2) with malonic acid gave (5) . Condensation of (1) with aromatic aldehydes afforded Schiffe base derivatives (6a,b) . Treatment of (1) with malononitrile, ethyl cyanoacetate and acetonitrile resulted the formation of pyridine derivatives (7a,b,c) . The reaction of (1) with urea and thiourea gave compound (8) . Condensation of (1) with o-phenylenediamine and o-aminophenol gave compound (9) . Reaction of (1) with nitrous acid followed by coupling with ethylacetoacetate afforded (10) . Bromination of (10) gave bromo derivative (11) . The structures of the hitherto unknown compounds have been confirmed by analytical and spectral methods . The newly synthesized compounds were screened for antibacterial activity.

Ann Periodontol, 2003 Dec, 8(1), 182 - 92
Microbial identification in the management of periodontal diseases . A systematic review; Listgarten MA et al.; BACKGROUND: Our understanding of the complexity of the oral microbiota continues to improve as new technologies, such as the analysis of 16S rRNA bacterial genes, are utilized . Despite the difficult of cataloguing all microorganisms and determining their pathogenic potential, some species, mostly members of the resident oral microbiota, have been identified as likely periodontal pathogens . However, for microbial diagnosis to be of value, it needs to affect disease diagnosis and/or treatment planning as well as result in superior treatment outcomes and/or provide an economic benefit to the patient . RATIONALE: The purposes of this systematic review were to determine if microbial identification influences periodontal patient management and whether treatment outcomes are better compared to patients whose treatment plans are developed without this information . FOCUSED QUESTION: In patients with periodontal diseases, does microbial identification influence patient management compared to treatment prescribed without this information? SEARCH PROTOCOL: The MEDLINE database was searched for clinical studies in English from 1991 through 2002 by 2 investigators . Hand searches were performed on the Journal of Clinical Periodontology, Journal of Periodontology, Journal of Periodontal Research, Oral Microbiology and Immunology, and Periodontology 2000 . In addition, directors of diagnostic laboratories were contacted about unpublished data . SELECTION CRITERIA: INCLUSION CRITERIA: Articles in which bacterial identification influenced patient treatment were preferred as were those reporting longitudinal data demonstrating a direct relationship between the presence or absence of certain bacteria and subsequent alterations in clinical variables . Because of the limited number of studies, all articles, including case reports, were considered . EXCLUSION CRITERIA: Review articles without original data were excluded, although references were examined for possible inclusion . Articles reporting data showing associations between certain microorganisms and disease or health that did not affect treatment were excluded . Clinical trials testing antibacterial agents for their ability to enhance mechanical debridement were not included since bacterial identification had little effect on drug selection or experimental group assignment . Articles dealing with implants rather than natural teeth were omitted . DATA ANALYSIS AND COLLECTION: The heterogeneity of the published data precludes any meaningful pooling of data or meta-analysis . The pertinent literature, including relevant variables of plaque, gingivitis, and bleeding on probing scores; probing depth; clinical attachment level; number of lost teeth; and microbial changes; and patient-centered outcomes including decrease in morbidity, reduced need for surgery, and duration and cost of treatment are summarized . MAIN RESULTS: 1 . There was a lack of articles with a high evidence rating; most pertinent articles were either case reports or case series without controls . 2 . Because reports were heterogeneous regarding study design, patient selection, and data collection, meta-analysis was not feasible and results are summarized in tabular format . 3 . This report is based on a total of 24 studies, representing a total patient population of approximately 835 . 4 . Thirteen studies reported on microbiological identification as an aid in treatment planning . 5 . Eleven studies reported a differential clinical response depending on the detection or lack of detection of specific organisms . REVIEWERS' CONCLUSIONS: 1 . The published material suggests that microbiological monitoring may be useful in management of selected patients who do not respond to standard therapy . 2 . Some practitioners consider microbial identification a valuable adjunct to managing patients with certain forms of periodontitis, although there is a lack of strong evidence to this effect . 3 . Additional research is needed to address this issue.

Eur J Immunol, 2004 Jan, 34(1), 174 - 83
Pulmonary tuberculosis in BALB/c mice with non-functional IL-4 genes: changes in the inflammatory effects of TNF-alpha and in the regulation of fibrosis; Hernandez-Pando R et al.; In BALB/c mice, as in man, progressive pulmonary tuberculosis is accompanied by increasing expression of IL-4 . Therefore we have used BALB/c mice with disrupted IL-4 genes (IL-4(-/-)) to investigate the role of IL-4 in pulmonary tuberculosis, with particular emphasis on the toxicity of TNF-alpha and on fibrosis, both of which are neglected aspects of human tuberculosis . Delayed-type hypersensitivity (DTH) sites in IL-4(+/+) mice were sensitive to the toxicity of locally injected TNF-alpha, whereas DTH sites in IL-4(-/-) mice were not . However, intravenous administration of IL-4 to IL-4(-/-) mice restored the sensitivity of the DTH sites to pro-inflammatory effects of TNF-alpha . In late disease, the lungs of IL-4(+/+) mice expressed low IFN-gamma, but high TGF-beta and IL-4, correlating with fibrosis, detected as a high hydroxyproline content . In contrast, TGF-beta peaked 7 days after infection in the lungs of the IL-4(-/-) mice, and then fell to very low levels in the late disease, while IFN-gamma remained high . Accordingly, hydroxyproline content was reduced in infected IL-4(-/-) mice compared to IL-4(+/+) controls . In conclusion, the findings suggest that IL-4 has modestly detrimental effects on the antibacterial efficacy of the Th1 response, and larger effects on the toxicity of TNF-alpha, and on fibrosis.

Mol Cell, 2004 Feb 13, 13(3), 307 - 16
Repair of DNA covalently linked to protein; Connelly JC et al.; A potentially lethal form of DNA/RNA modification, a cleavage complex, occurs when a nucleic acid-processing enzyme that acts via a transient covalent intermediate becomes trapped at its site of action . A number of overlapping pathways act to repair these lesions and many of the enzymes involved are those that catalyze recombinational-repair processes . A protein, Tdp1, has been identified that reverses cleavage-complex formation by specifically hydrolyzing a tyrosyl-DNA phosphodiester bond . The study of these pathways is both interesting and pertinent as they modulate the effectiveness of many antitumor/antibacterial drugs that act by stabilizing cleavage-complexes in vivo.

Am J Physiol Lung Cell Mol Physiol, 2004 Jun, 286(6), L1302 - 10 Epub 2004 Feb 13.
Roles for early response cytokines during Escherichia coli pneumonia revealed by mice with combined deficiencies of all signaling receptors for TNF and IL-1; Mizgerd JP et al.; During infection, inflammation is essential for host defense, but it can injure tissues and compromise organ function . TNF-alpha and IL-1 (alpha and beta) are early response cytokines that facilitate inflammation . To determine the roles of these cytokines with overlapping functions, we generated mice deficient in all of the three receptors mediating their effects (TNFR1, TNFR2, and IL-1RI) . During Escherichia coli pneumonia, receptor deficiency decreased neutrophil recruitment and edema accumulation to half of the levels observed in wild-type mice . Thus these receptors contributed to maximal responses, but substantial inflammation progressed independently of them . Receptor deficiency compromised antibacterial efficacy for some infectious doses . Decreased ventilation during E . coli pneumonia was not affected by receptor deficiency . However, the loss of lung compliance during pneumonia was substantially attenuated by receptor deficiency . Thus during E . coli pneumonia in mice, the lack of signaling from TNF-alpha and IL-1 decreases inflammation and preserves lung compliance.

Mini Rev Med Chem, 2004 Feb, 4(2), 189 - 200
Antiviral sulfonamide derivatives; Supuran CT et al.; The sulfonamides constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, anti-carbonic anhydrase, diuretic, hypoglycemic, antithyroid and anticancer activity among others . A large number of structurally novel sulfonamide derivatives have ultimately been reported to show substantial antiviral activity in vitro and in vivo . The review summarizes recent classes of sulfonamides and related sulfonyl derivatives disclosed as effective such agents . Thus, at least some HIV protease inhibitors used clinically (amprenavir) or compounds in advanced clinical trials (tipranavir, TMC-126, TMC-114, etc.) possess sulfonamide moieties in their molecules, whereas a very large number of other derivatives are constantly being synthesized and evaluated in order to obtain compounds with less toxicity or activity against drug-resistant viruses . Several non nucleoside HIV reverse transcriptase or HIV integrase inhibitors containing sulfonamide groups were also reported . Another approach to inhibit the growth of retroviruses, including HIV, targets the ejection of zinc ions from critical zinc finger viral proteins, which has as a consequence the inhibition of viral replication in the absence of mutations leading to drug resistance phenotypes . Most compounds with antiviral activity possessing this mechanism of action incorporate in their molecules primary sulfonamide groups . Finally, some small molecule chemokine antagonists acting as HIV entry inhibitors also possess sulfonamide functionalities in their scaffold.

Org Lett, 2004 Feb 19, 6(4), 557 - 60
Biocidal activity of polystyrenes that are cationic by virtue of protonation; Gelman MA et al.; {structure: see text} Poly(1) kills bacteria (Gram-positive and -negative) and lyses human erythrocytes; this biocidal profile is similar to that of the peptide toxin mellitin . Poly(1) has antibacterial activity comparable to that of a potent derivative of the host defense peptide magainin II, but lacks magainin's selectivity for bacteria over erythrocytes . An analogous N-quaternized polymer, poly(3), is less biocidal than poly(1), suggesting that reversible N-protonation leads to greater biocidal activity than does irreversible N-quaternization.

Food Chem Toxicol, 2004 Mar, 42(3), 389 - 95
Peri- and postnatal developmental toxicity of the fluoroquinolone antibacterial DW-116 in rats; Kim JC et al.; DW-116 is a fluoroquinolone antibacterial developed by Dong-Wha Pharmaceutical Industry Co . The aim of this study is to determine the potential adverse effects of this chemical on pregnancy, delivery and lactation of dams and on peri- and postnatal development of F1 offspring . The test chemical was orally administered to pregnant rats from day 16 of pregnancy, through parturition and throughout the period of lactation up to weaning (postnatal day 21) at dose levels of 0, 10, 50, or 250 mg/kg/day . The progeny were examined at birth and subsequently to weaning . Mortality, body weight change, physical signs of postnatal development (pinna detachment, incisor eruption, fur development, eye opening, testis descent and vaginal opening) and behavioral function (righting reflex, negative geotaxis, grip-strength, pupillary reflex, acoustic startle response, rotating rod test, open field test and water-filled T-maze test) were evaluated . When the exposed offspring reached maturity (11 weeks old) their reproductive capacity was assessed . Maternal toxicity was observed only in the highest dose group and was limited to decreased food consumption during the late stage of pregnancy . However, this change was not observed during the lactation period . There were no adverse effects on mortality, clinical signs, body weight, necropsy findings, organ weight of dams in any treatment group . No adverse effects on the offspring were seen with the low and middle doses tested, but the highest dose increased postnatal mortality . The number of stillborn was also increased at the highest dose but the difference was not statistically significant . Meanwhile, no treatment-related effects were observed in clinical sign, developmental and behavioral landmarks and necropsy findings at any dose levels tested . There were no treatment-related effects on the mating of the F1 generation and resulting F2 offspring . The results of this study indicate that the peri- and postnatal administration of DW-116 to female rats results in an increase in postnatal mortality at a minimally maternotoxic dose, i.e., 250 mg/kg/day . Under the experimental conditions, the no-observed-adverse-effect level for peri- and postnatal developmental toxicity was considered to be 50 mg/kg/day.

Int Endod J, 2004 Feb, 37(2), 132 - 8
Endodontic treatment of primary teeth using a combination of antibacterial drugs; Takushige T et al.; AIM: To evaluate the clinical outcome of 'Lesion Sterilization and Tissue Repair' (LSTR) therapy for endodontic treatment of primary teeth . METHODOLOGY: A mixture of metronidazole, ciprofloxacin, and minocycline (3Mix) in ointment (macrogol mixed with propylene glycol: MP) or in a root canal sealer was used to disinfect infected root canals of 56 patients aged 4-18 years . Out of a total of 87 primary teeth, 81 cases had physiologic root resorption . A total of 54 radiolucent periradicular lesions were present . The root canals were not prepared before or after disinfection . 3Mix medicament (3Mix-MP/3Mix-sealer) was placed at orifices of root canals or on the bottom of pulp chambers, and then sealed with glass-ionomer cement and further reinforced by a composite resin inlay prepared using a direct method and cemented with resin . RESULTS: In all cases, clinical symptoms such as gingival swelling (52 cases), sinus tracts (22 cases), induced dull pain (3 cases), spontaneous dull pain (26 cases), and pain on biting (46 cases) disappeared after treatment, although in four cases clinical signs and symptoms were finally resolved only after retreatment using the same procedures . Thus, gingival abscesses and fistulae, if present, disappeared after a few days . Successor permanent teeth erupted without any disorders, or were found radiographically to be normal and in the process of eruption . All the cases were evaluated as successful . The mean function time of the primary teeth was 680 days (range: 68-2390 days), except for one case in which the successor permanent tooth was congenitally missing . CONCLUSION: Primary teeth with periradicular lesions with or without physiologic root resorption were treated successfully by the LSTR endodontic therapy.

J Gastroenterol, 2004 Jan, 39(1), 61 - 3
Inhibitory effect of green tea catechins in combination with sucralfate on Helicobacter pylori infection in Mongolian gerbils; Takabayashi F et al.; BACKGROUND: The occurrence of antibiotic-resistant Helicobacter pylori has been reported . It is desirable to develop an effective method to prevent the occurrence of resistant strains of Helicobacter pylori . Green tea catechins (GTCs) have been reported to have an antibacterial effect . Therefore, the possibility of eradicating Helicobacter pylori by the oral administration of GTCs was investigated . METHODS: Solutions of GTCs and solutions of GTCs adsorbed to sucralfate (GTC-scf), at concentrations of 20 mg GTCs and/or 20 mg sucralfate/ml were prepared . Then 1 ml of the GTC-scf or the GTC solution was administered daily, for 10 days to Mongolian gerbils infected with Helicobacter pylori . Then the stomachs were extirpated and homogenized . The homogenate was spread on selective medium plates . After 5-day culture, colony-forming units (CFU) of Helicobacter pylori were counted . RESULTS: The CFU of Helicobacter pylori was significantly decreased by GTC-scf . CONCLUSIONS: GTC-scf may have a bactericidal effect on Helicobacter pylori infection.

Med Trop (Mars), 2003, 63(4-5), 491 - 7
{Antiparasitic treatments in pregnant women and in children in 2003}; Richard-Lenoble D et al.; Like antibacterial agents, antiparasite drugs for pregnant women and children must be chosen in function of the stage of pregnancy, age of the child, and expected benefit-risk ratio . While no agent is totally safe, there are few absolute contraindications . Most zones of serious endemic parasite disease are located in developing countries where parasite, bacterial, or viral conditions combined with poor nutrition treatment make it necessary to treat disease in a complex pathogenic environment that weakens pregnant women and children with multiple parasite infections . In both temperate and tropical zones, there have been few real therapeutic advances involving release of new products on the market or development of new indications for existing products . Constant appearance and extension of hematozoa resistance to conventional and even more recent antimalarial agents have prompted research to find new active drugs and long-lasting treatment combinations . Real therapeutic breakthroughs have resulted from the need to develop safe drugs without substantial side-effects for single-dose use in control programs against endemic parasite diseases in mass populations including pregnant women and young children in tropical zones . There are several notable examples in the field of major verminous diseases . Ivermectin is a versatile drug that can be used against filariasis as well as for management of intestinal worms or ectoparasitosis in temperate and tropical countries . Praziquantel is an important advance in platyhelminthiasis, especially bilharziais . Triclabendazole, the latest addition to the benzimidazole family, has shown promise as a substitute for bithionol, that is difficult to procure and not recommended in pregnant women, for treatment distomiasis occurring in pregnant women and children . Other examples include albendazole against giardiasis, nitazoxamide against cryptosporidiosis, artemisinine against bilharziasis, and paramomycine, not recommended in pregnant women, against leishmaniasis.

Chem Pharm Bull (Tokyo), 2004 Feb, 52(2), 178 - 85
Synthesis, anticancer and antibacterial activity of some novel mononuclear Ru(II) complexes; Mazumder UK et al.; In search of potential anticancer drug candidates in ruthenium complexes, a series of mononuclear ruthenium complexes of the type {Ru(phen)(2)(nmit)}Cl(2) (Ru1), {Ru(bpy)(2)(nmit)}Cl(2) (Ru2), {Ru(phen)(2)(icpl)}Cl(2) (Ru3), Ru(bpy)(2)(icpl)}Cl(2) (Ru4) (phen=1,10-phenanthroline; bpy=2,2'-bipyridine; nmit=N-methyl-isatin-3-thiosemicarbazone, icpl=isatin-3-(4-Cl-phenyl)thiosemicarbazone) and {Ru(phen)(2)(aze)}Cl(2) (Ru5), {Ru(bpy)(2)(aze)}Cl(2) (Ru6) (aze=acetazolamide) and {Ru(phen)(2)(R-tsc)}(ClO(4))(2) (R=methyl (Ru7), ethyl (Ru8), cyclohexyl (Ru9), 4-Cl-phenyl (10), 4-Br-phenyl (Ru11), and 4-EtO-phenyl (Ru12), tsc=thiosemicarbazone) were prepared and characterized by elemental analysis, FTIR, (1)H-NMR and FAB-MS . Effect of these complexes on the growth of a transplantable murine tumor cell line (Ehrlich Ascites Carcinoma) and their antibacterial activity were studied . In cancer study the effect of hematological profile of the tumor hosts have also been studied . In the cancer study, the complexes Ru1-Ru4, Ru10 and Ru11 have remarkably decreased the tumor volume and viable ascitic cell count as indicated by trypan blue dye exclusion test (p<0.05) . Treatment with the ruthenium complexes prolonged the lifespan of Ehrlich Ascites Carcinoma (EAC) bearing mice . Tumor inhibition by the ruthenium chelates was followed by improvements in hemoglobin, RBC and WBC values . All the complexes showed antibacterial activity, except Ru5 and Ru6 . Thus, the results suggest that these ruthenium complexes have significant antitumor property and antibacterial activity . The results also reflect that the drug does not adversely affect the hematological profiles as compared to that of cisplatin on the host.

Rev Med Chir Soc Med Nat Iasi, 2003 Oct-Dec, 107(4), 737 - 42
{Drug residues in food of animal origin}; Gavat V et al.; This paper reviews literature data on the stability of drug residues in food of animal origin . It was investigated the most important antibacterial, antihelminthic and sedative drugs and growth promoters used in food/producing animal treatments . The effects of storage (at -20 degrees C, 4 degrees C and temperature room) and a range of cooking processes (boiling, frying, roasting, grilling, microwaving) on residues was studied . The results are summarized in tables and showed that degradation and biological activity were varied between 0 and 100%.

Postgrad Med, 2004 Jan, 115(1), 13 - 9
Acute sinusitis . When--and when not--to prescribe antibiotics; Leggett JE; Clinical diagnosis of acute sinusitis is troublesome because it involves use of a cluster of diagnostic criteria that have only moderate sensitivity . Ancillary testing with radiography or antral puncture is impractical, expensive, and usually unnecessary in the primary care setting . Antibiotic therapy is not beneficial for most patients in whom acute sinusitis is suspected, even when radiographic abnormalities are found . Simple management algorithms and patient information are now available to aid primary care physicians in offering appropriate therapeutic measures and reassuring patients who are expecting "'a pill for every ill' when that pill is an antibacterial."

Phytochemistry, 2004 Feb, 65(4), 475 - 80
Ascosonchine, the enol tautomer of 4-pyridylpyruvic acid with herbicidal activity produced by Ascochyta sonchi; Evidente A et al.; A new phytotoxic enol tautomer of 4-pyridylpyruvic acid, named ascosonchine, was isolated from the culture filtrate of Ascochyta sonchi . Such a leaf pathogen is a potential biocontrol agent of Sonchus arvensis, a perennial herbaceous weed occurring throughout the temperate regions of the world . Ascosonchine, characterised as (Z)-2-hydroxy-3-(4-pyridyl)-2-propenoic acid by spectroscopic methods, showed selective herbicidal properties, that are not associated with antibacterial, antifungal or zootoxic activities.

Clin Microbiol Infect, 2004 Feb, 10(2), 163 - 70
Ampicillin + sulbactam vs clindamycin +/- cephalosporin for the treatment of aspiration pneumonia and primary lung abscess; Allewelt M et al.; Aspiration pneumonia, necrotising pneumonia and primary lung abscess are complications arising from the aspiration of infectious material from the oral cavity or stomach . There is limited information on optimal antibacterial therapeutic regimens . Patients with pulmonary infection following aspiration (n = 95) were included in a prospective, open, randomised, comparative multicentre trial to compare the safety, clinical and bacteriological efficacy of ampicillin + sulbactam vs . clindamycin +/- cephalosporin . Treated patients (n = 70) received sequential antibiotic therapy with either ampicillin + sulbactam (n = 37) or clindamycin (n = 33), with or without a second- or third-generation cephalosporin, administered until the complete resolution of clinical and radiological abnormalities . Definite or presumptive pathogens were isolated from 58 patients . Mean duration of therapy was 22.7 days for ampicillin + sulbactam and 24.1 days for clindamycin . In patients treated with ampicillin + sulbactam, the clinical response was 73.0% at the end of therapy and 67.5% 7-14 days after therapy . For clindamycin, the rates were 66.7% and 63.5%, respectively . Bacteriological response was similar in both treatment arms . Nine patients died (12.9%), with a Simplified Acute Physiology Score of > 30 points being the only significant predictive factor for therapeutic failure . Ampicillin + sulbactam and clindamycin +/- cephalosporin were both well-tolerated and proved equally effective in the treatment of aspiration pneumonia and lung abscess.

Biopolymers, 2004 Feb 5, 73(2), 229 - 41
Conformational and structural analysis of the equilibrium between single- and double-strand beta-helix of a D,L-alternating oligonorleucine; Navarro E et al.; Alternating sequences of D and L residues in peptides are directly related to the formation of several kinds of regular helical conformations usually called beta-helices . The major feature of these structures is that they can be associated with the transmembrane ion-conducting channel activity in some natural antibacterial peptides . The study of alternating D,L synthetic peptides is critical to understand how factors such as surrounding media, main chain length, type of side chain and terminal groups, among others, can determine the adoption of a specific kind of beta-helix . Early studies pointed out that the peptides Boc-(D-NLeu-L-NLeu)(6)-D-MeNLe-L-Nl-D-Nl-L-Nl-OMe (Boc: tert-butyloxycarbonyl) and Boc-L-Nle-(D-Nle-L-Nle)(5)-D-MeNle-L-Nle-D-Nle-L-Nle-OMe adopt in chloroform a unique detectable conformation single beta(4.4)- and double beta(5.6) upward arrow downward arrow -helix, respectively . The influence of terminal groups on the final stable conformation of N-formylated peptides has been studied in this work . The initial basic NMR data analysis of a synthetic alternating D,L-oligopeptide with ten norleucines, N-methylated on the residue 7 and having HCO- and -OMe as terminal groups clearly indicates the coexistence of two different conformations in equilibrium . NMR data and molecular dynamics calculations point to a dimeric antiparallel beta-helix structure beta(5.6) upward arrow downward arrow for the main conformation . On the other hand, NMR data suggest a single beta-helix structure beta(4.4) for the second conformation . Finally, a thermodynamic analysis of the equilibrium between both conformations has been carried out by one-dimensional NMR measurements at ten different temperatures . The temperature at which 50% of dimer conformation is dissociated is 319 K . In addition, the dimer-monomer equilibrium curve obtained shows a DeltaG>0 for the whole range of studied temperatures, and its behavior can be considered similar to the thermodynamic denaturation protein processes .

Mini Rev Med Chem, 2004 Jan, 4(1), 93 - 109
Beta-lactams in the new millennium . Part-II: cephems, oxacephems, penams and sulbactam; Singh GS; Beta-lactam ring-containing compounds such as penicillins, ampicillin, amoxicillin, cephalosporins and carbapenems are among the most famous antibiotics . This article reviews the recent developments in study of cephems, oxacephems, penams and sulbactam . Many of the compounds reviewed have potential antibacterial activity, even against resistant strains such as MRSA, and enzyme inhibitory activity.

Mini Rev Med Chem, 2004 Jan, 4(1), 69 - 92
Beta-lactams in the new millennium . Part-I: monobactams and carbapenems; Singh GS; Beta-lactam ring-containing compounds such as penicillins, ampicillin, amoxicillin, cephalosporins and carbapenem are among the most famous antibiotics . This article reviews the recent developments in the study of such compounds . The introductory paragraph, which highlights the significance of the subject and cites most of the leading references of the previous century, is followed by an overview of beta-lactams and some novel methodologies for the synthesis of bi-, tri- and polycyclic derivatives . The rest of the sections deal with design, synthesis and biological activity of monobactams and carbapenems . Many of them have potential antibacterial activity, even against some resistant strains, and enzyme inhibitory activity.

Mini Rev Med Chem, 2004 Jan, 4(1), 31 - 9
The wide pharmacological versatility of semicarbazones, thiosemicarba-zones and their metal complexes; Beraldo H et al.; The more significant bioactivities of a variety of semicarbazones (anti-protozoa, anticonvulsant) and thiosemicarbazones (antibacterial, antifungal, antitumoral, antiviral) and their metal complexes are reviewed together with proposed mechanisms of action and structure-activity relationships . Clinical or potential pharmacological applications of these versatile compounds are discussed.

Acta Microbiol Immunol Hung, 2003, 50(4), 385 - 93
QSAR analysis of antibacterial activity of some 4-aminodiphenylsulfone derivatives; Agrawal VK et al.; QSAR studies on a set of 36 congeners of 4-aminodiphenylsulfone derivatives with measured inhibition potencies of dihydropterate synthase were made using multiple regression analysis . Conformational entropy in combination with indicator parameters gave excellent results.

Planta Med, 2003 Dec, 69(12), 1159 - 62
Chemical composition and antibacterial activity of essential oil of Artemisia iwayomogi; Yu HH et al.; The chemical composition of the essential oil from Artemisia iwayomogi Kitamura was analyzed by means of GC and GC-MS . Eighty-five constituents were identified representing 96.23 % of the total oil . Camphor (19.31 %), 1,8-cineole (19.25 %), borneol (18.96 %), camphene (4.64 %), and beta-caryophyllene (3.46 %) were found to be the major components . Furthermore, the oil exhibited antibacterial activity against six Gram-(+) and six Gram-(-) bacteria in tests using the broth dilution method.

Acta Trop, 2004 Feb, 89(3), 351 - 6
Therapeutic responses to antimalarial and antibacterial drugs in vivax malaria; Pukrittayakamee S et al.; Plasmodium vivax is the most prevalent malaria infection and is an important cause of morbidity in Central and South America and Asia . P . vivax is generally sensitive to the common antimalarial drugs but high level resistance to chloroquine and/or pyrimethamine has been documented in some geographic locations . In the studies reviewed here, the therapeutic responses to antimalarial and antibacterial drugs in vivax malaria have been assessed in the Bangkok Hospital for Tropical Diseases . The evaluated drugs consisted of the eight most widely used antimalarial drugs and anti-bacterial drugs that possess antimalarial activities (tetracycline, doxycycline, clindamycin or azithromycin) . The activities of these drugs in descending order of parasite clearance times were artesunate, artemether, chloroquine, mefloquine, quinine, halofantrine, primaquine, followed by the antibacterial drugs and lastly sulfadoxine-pyrimethamine . Clinical responses to sulfadoxine-pyrimethamine were also poor with evidence of high grade resistance in 42% of the patients . Of the four antibacterial drugs, clindamycin was more effective than azithromycin and can be an alternative to the tetracyclines . Except for chloroquine and mefloquine which have long plasma half lives and may therefore suppress first relapses, the cumulative cure rates for the short acting antimalarial drugs were similar . Double infection with Plasmodium falciparum was common and usually manifested 3-4 weeks following clearance of vivax malaria . The prevalence of cryptic falciparum malaria was 8-15% and was higher in patients treated with less potent antimalarial drugs . Follow-up studies have revealed that the relapse time in Thai patients with vivax malaria is on average only 3 weeks, but can be suppressed by the slowly eliminated antimalarial drugs such as chloroquine and mefloquine . For accurate comparison of relapse/recrudescence rates in vivax malaria, at least 2 month's follow-up is required . It can be concluded that in malarious areas of Thailand, double infection with P . falciparum and P . vivax is common affecting at least 25% of the patients and usually manifests as sequential illnesses . P . vivax in Thailand is sensitive to chloroquine but has acquired high grade resistance to sulfadoxine-pyrimethamine.

Biochemistry, 2004 Feb 3, 43(4), 1111 - 7
DNA enzyme generated by a novel single-stranded DNA expression vector inhibits expression of the essential bacterial cell division gene ftsZ; Tan XX et al.; Rapid emergence of antibiotic-resistant bacterial pathogens has created urgent demand for the discovery and development of new antibacterial agents directed toward novel targets . Antisense oligodeoxynucleotides (AS-ODN) and their modified forms have been utilized to block gene expression in bacterial cells, showing potential for developing highly specific and efficacious antibacterial agents . In this study, a tetracycline-regulated expression vector was developed for generating single-stranded DNA (ssDNA) of a desired target sequence in bacterial cells . This inducible ssDNA expression vector was tested for producing a DNA enzyme designed to specifically cleave ftsZ mRNA . Our results indicate that the expressed DNA enzyme molecules not only repress ftsZ gene expression and but also inhibit bacterial cell proliferation . Although we believe that the cleavage of ftsZ mRNA by the expressed DNA enzyme molecules is responsible for the inhibitory effects on ftsZ gene expression and bacterial cell proliferation, the antisense mechanism could also be responsible for the biological effects . The ability of this ssDNA expression system to selectively modulate gene expression may provide a powerful strategy in determining the contribution of a given gene product to bacterial growth or pathogenesis and opens a new venue for developing antibacterial agents.

Biochemistry, 2004 Feb 3, 43(4), 937 - 44
Investigating the importance of the flexible hinge in caerin 1.1: solution structures and activity of two synthetically modified caerin peptides; Pukala TL et al.; Caerin 1.1 is a potent broad-spectrum antibacterial peptide isolated from a number of Australian frogs of the Litoria genus . In membrane-like media, this peptide adopts two alpha-helices, separated by a flexible hinge region bounded by Pro15 and Pro19 . Previous studies have suggested that the hinge region is important for effective orientation of the two helices within the bacterial cell membrane, resulting in lysis via the carpet mechanism . To evaluate the importance of the two Pro residues, they were replaced with either Ala or Gly . The antibacterial activity of these two peptides was tested, and their three-dimensional structures were determined using two-dimensional NMR spectroscopy and restrained molecular dynamics calculations . The resulting structures indicate that the central hinge angle decreases significantly upon replacement of the Pro residues with Gly and to a further extent with Ala . This trend was mirrored by a corresponding decrease in antibiotic activity, further exemplifying the necessity of the hinge in caerin 1.1 and related peptides . In a broader context, the use of Pro, Gly, and Ala variants of caerin 1.1 has enabled the relationship between conformational flexibility and activity to be directly investigated in a systematic manner.

J Dent Res, 2004 Feb, 83(2), 115 - 9
Antibacterial titanium plate anodized by being discharged in NaCl solution exhibits cell compatibility; Shibata Y et al.; Implant surfaces should be modified to achieve excellent cell compatibility as well as antibacterial activity . Our previous study demonstrated that titanium plates anodized by being discharged in NaCl (Ti-Cl) exhibited high antibacterial activity . Since Ti-Cl was prepared with a NaCl solution, we hypothesized that Ti-Cl would exhibit low toxicity toward cells . The aims of this study were to characterize the surface of Ti-Cl and investigate the cell compatibility (MC3T3-E1 and L929 cells) of Ti-Cl . The results demonstrated that, since the TiCl(3) formed on the Ti-Cl surface was hydrolyzed into HCl, HClO, and TiOH after immersion in pure distilled water, TiCl(3) contributed to the antibacterial activity of Ti-Cl . On the other hand, TiO formed on the Ti-Cl surface enhanced cell extension and cell growth through a larger adsorption of fibronectin compared with the pure titanium control . These findings suggest that antibacterial titanium is a promising material for use in dental implant systems.

Bioorg Med Chem Lett, 2004 Feb 9, 14(3), 735 - 8
Vancomycin disulfide derivatives as antibacterial agents; Mu Y et al.; A series of lipidated vancomycin analogues 1 bearing disulfide bonds within their lipid chains was designed and synthesized to optimize their ADME profiles while retaining antibacterial potency . These compounds exhibited good activity against resistant organisms and low accumulation in tissues such as kidney and liver.

Bioorg Med Chem Lett, 2004 Feb 9, 14(3), 653 - 6
Synthesis and antifungal activities of phenylenedithioureas; Phuong T et al.; A total of 20 new phenylenedithiourea derivatives was synthesized by reaction of phenylenediisothiocyanates with aromatic amines as aminobenzoic, aminosalicylic acid and their derivatives . Their chemical structures were confirmed by elemental analysis, IR spectrometry and 1H NMR . The compounds were screened for in vitro antifungal, antibacterial activities and some of them have strong antifungal activities comparable to the activity observed for ketoconazole.

J Biol Chem, 2004 Apr 2, 279(14), 13402 - 11 Epub 2004 Jan 21.
Furin is a chemokine-modifying enzyme: in vitro and in vivo processing of CXCL10 generates a C-terminally truncated chemokine retaining full activity; Hensbergen PJ et al.; Chemokines comprise a class of structurally related proteins that are involved in many aspects of leukocyte migration under basal and inflammatory conditions . In addition to the large number of genes, limited processing of these proteins by a variety of enzymes enhances the complexity of the total spectrum of chemokine variants . We have recently shown that the native chemokine CXCL10 is processed at the C terminus, thereby shedding the last four amino acids . The present study was performed to elucidate the mechanism in vivo and in vitro and to study the biological activity of this novel isoform of CXCL10 . Using a combination of protein purification and mass spectrometric techniques, we show that the production of C-terminally truncated CXCL10 by primary keratinocytes is inhibited in vivo by a specific inhibitor of pro-protein convertases (e.g . furin) but not by inhibition of matrix metalloproteinases . Moreover, CXCL10 is processed by furin in vitro, which is abrogated by a mutation in the furin recognition site . Using GTPgammaS binding, Ca(2+) mobilization, and chemotaxis assays, we demonstrate that the C-terminally truncated CXCL10 variant is a potent ligand for CXCR3 . Moreover, the inverse agonist activity on the virally encoded receptor ORF74 and the direct antibacterial activity of CXCL10 are fully retained . Hence, we have identified furin as a novel chemokine-modifying enzyme in vitro and most probably also in vivo, generating a C-terminally truncated CXCL10, which fully retains its (inverse) agonistic properties.

Bioorg Med Chem, 2004 Feb 1, 12(3), 571 - 6
In vitro study of some medicinally important Mannich bases derived from antitubercular agent; Joshi S et al.; Biologically active Mannich bases with heteroaromatic ring system have been synthesised employing Mannich reaction of isonicotinyl hydrazide with various sulphonamides/secondary amines . They were analysed by elemental analysis and characterized by uv, ir, 1H nmr spectroscopic studies . The Mannich bases were screened for their antibacterial activity against various gram positive and gram negative bacteria and were analyzed statistically . The results have shown that the compounds are quiet active against pathogens under study and were nontoxic.

Microbes Infect, 2004 Jan, 6(1), 51 - 7
Hepatocyte growth factor inhibits intrinsic antibacterial activity of Madin-Darby canine kidney cells; Wade BK et al.; We investigated whether or not polarized renal epithelial cells produce antibacterial factors, which aid in host defense at the cell surface of renal epithelium . A model of polarized Madin-Darby canine kidney (MDCK) epithelial cells grown on filters was used to test for the presence of apically or basolaterally secreted factors on the growth of non-virulent (XL1-Blue) and uropathogenic (J96) strains of Escherichia coli (E . coli) . Growth of both XL1-Blue and J96 strains of E . coli in medium on the apical and basolateral surface of MDCK cells was inhibited as compared to bacterial growth in medium not exposed to MDCK cells . The inhibition of bacterial growth was similar in both apical and basolateral surface medium . Pretreatment of MDCK cells with hepatocyte growth factor (HGF) blunted the inhibition of XL1-Blue and J96 growth in apical and basolateral surface medium as compared to growth in medium on the surfaces of untreated MDCK cells . Immunofluorescent analysis demonstrated the presence of beta-defensin isoforms 1-3 in MDCK cells, with isoform 1 being the most prevalent form observed . HGF treatment reduced the amount of immunoreactive beta-defensin-1 in MDCK cells . These data demonstrate that polarized renal epithelium produce antibacterial factors . The renotropic growth factor HGF inhibits these antibacterial factors . beta-defensins may contribute to this antibacterial activity and play an important role in renal epithelial resistance to bacterial infections.

J Pharm Pharmacol, 2003 Dec, 55(12), 1667 - 72
Study of inhibition of CYP2A6 by some drugs derived from quinoline; Hirano Y et al.; CYP2A6 metabolizes coumarin to 7-hydroxycoumarin showing fluorescence, as measured by fluorometry . Firstly, we measured the inhibition of coumarin 7-hydroxylase of cDNA-expressed human CYP2A6 and in bovine liver microsomes, by quinoline and fluoroquinolines (FQ) . Quinoline, 5-FQ, 6-FQ and 8-FQ inhibited activity but 3-FQ showed little inhibition . This suggests that the position 3 of quinoline is a recognition site for CYP2A6 . We found similar patterns of coumarin 7-hydroxylase activity with human pooled liver microsomes . The level of CYP2A6 in human and bovine microsomes is the same as that detected by immunological titration with monoclonal antibody against CYP2A6 . Secondly, we studied the inhibition of CYP2A6 with clinically used drugs of quinoline compounds, such as norfloxacin as an antibacterial agent, quinidine as an antiarrhythmic agent, quinine and chloroquine as antimalaria agents and rebamipide as an anti-ulcer agent . IC50 values (concentration producing 50% inhibition in activity) of norfloxacin, rebamipide and chloroquine at mM concentrations showed them to possess almost no inhibitory activity or influence on drug interaction . Meanwhile, the IC50 value of quinidine was 1.12 mM . The IC50 value of quinine was 160 microM with weak inhibition, suggesting that quinine, at a high dose, influences the metabolism of substrates for CYP2A6 by drug-drug interaction . These results also show that CYP2A6 discriminates the structure difference between the diastereoisomers quinidine and quinine.

Ann Trop Paediatr, 2003 Dec, 23(4), 293 - 9
Neonatal morbidity and mortality in a Tanzanian tertiary care referral hospital; Klingenberg C et al.; In developing countries, neonatal mortality accounts for 50-70% of infant mortality . The purpose of this study was to describe morbidity and mortality patterns, with a focus on neonatal infections, in a Tanzanian special care baby unit (SCBU) . During a 3-month period, 246 consecutive admissions to the SCBU at Kilimanjaro Christian Medical Centre were audited . Prematurity, low birthweight and suspected infection accounted for 61% of all admissions . The overall mortality rate was 19%, but varied considerably according to gestational age, birthweight and diagnosis . Thirty-one neonates (two-thirds of all deaths) died during the 1st 24 hours of life . Of 27 infants admitted on grounds of perinatal asphyxia, 11 (41%) died, and, of 19 infants with a gestational age <31 weeks, 13 (68%) died . More than two-thirds of all infants were treated with antibiotics . Septicaemia confirmed by blood culture was found in 16 cases . The susceptibility pattern of bacterial isolates did not indicate high rates of resistance to commonly used antibacterial agents . A reduction in the number of preterm deliveries and improved perinatal care to avoid and treat perinatal asphyxia would be the two most important measures in reducing neonatal mortality in this setting.

J Nat Prod, 2004 Jan, 67(1), 31 - 6
Africane-type sesquiterpenoids from the Argentine liverwort Porella swartziana and their antibacterial activity; Bovi Mitre G et al.; Seven africanes (1, 2a,b, 3-6), two of them new (1, 2a), three secoafricanes (7-9), one of them new (7), and two norsecoafricanes (10, 11a), one of them new (10), all of them swartzianin-type, have been isolated from an Argentine collection of the endemic liverwort Porella swartziana . The structures of the new compounds were established by extensive 1D and 2D NMR spectroscopic data . Absolute configurations of compounds 2a, 2b, and 10 were derived on the basis of CD spectra . The compounds were tested for activity against a variety of microbes, but none were found to exhibit significant antibacterial activity.

Chem Soc Rev, 2004 Jan 10, 33(1), 43 - 63 Epub 2003 Dec 05.
Dendrimers in drug research; Boas U et al.; Dendrimers are versatile, derivatisable, well-defined, compartmentalised chemical polymers with sizes and physicochemical properties resembling those of biomolecules e.g . proteins . The present critical review (citing 158 references) briefly describes dendrimer design, nomenclature and divergent/convergent dendrimer synthesis . The characteristic physicochemical features of dendrimers are highlighted, showing the effect of solvent pH and polarity on their spatial structure . The use of dendrimers in biological systems are reviewed, with emphasis on the biocompatibility of dendrimers, such as in vitro and in vivo cytotoxicity, as well as biopermeability, biostability and immunogenicity . The review deals with numerous applications of dendrimers as tools for efficient multivalent presentation of biological ligands in biospecific recognition, inhibition and targeting.Dendrimers may be used as drugs for antibacterial and antiviral treatment and have found use as antitumor agents . The review highlights the use of dendrimers as drug or gene delivery devices in e.g . anticancer therapy, and the design of different host-guest binding motifs directed towards medical applications is described.Other specific examples are the use of dendrimers as 'glycocarriers' for the controlled multimeric presentation of biologically relevant carbohydrate moieties which are useful for targeting modified tissue in malignant diseases for diagnostic and therapeutic purposes . Finally, the use of specific types of dendrimers as scaffolds for presenting vaccine antigens, especially peptides, for use in vaccines is presented.

Planta Med, 2003 Nov, 69(11), 1066 - 8
A new indolizinone from Polygonatum kingianum; Wang YF et al.; A new indolizinone, namely kinganone (1) together with 3-ethoxymethyl-5,6,7,8-tetrahydro-8-indolizinone (2) and isomucronulatol (3) were isolated from the rhizome of Polygonatum kingianum . Their structures were elucidated mainly on the basis of spectral data . Indolizinones 1 and 2 showed weak antibacterial and antifungal activities when compared to rifampicin and amphotericin, respectively, in the agar diffusion assay.

Can J Microbiol, 2003 Nov, 49(11), 669 - 74
Screening of nonpolyenic antifungal metabolites produced by clinical isolates of actinomycetes; Lemriss S et al.; The purpose of this work was to screen clinical isolates of actinomycetes producing nonpolyenic antifungals . This choice was made to limit the problem of rediscovery of well-known antifungal families, especially polyenic antifungals . One hundred and ten strains were tested, using two diffusion methods and two test media, against three yeast species and three filamentous fungi . Among 54 strains (49%) showing antifungal activity, five strains belonging to the genus Streptomyces were active against all test organisms and appeared promising . These results indicate that clinical and environmental isolates of actinomycetes could be an interesting source of antifungal bioactive substances . The production of nonpolyenic antifungal substances by these five active isolates was investigated using several criteria: antibacterial activity, ergosterol inhibition, and UV-visible spectra of active extracts . One active strain responded to all three selection criteria and produced potentially nonpolyenic antifungal metabolites . This strain was retained for further investigation, in particular, purification, structure elucidation, and mechanism of action of the active product.

Yao Xue Xue Bao, 2003 Oct, 38(10), 754 - 9
{Synthesis and in vitro antibacterial activities of new 3,5-disubstituted oxazolidinone compounds}; Meng QG et al.; AIM: To design and synthesize new oxazolidinone antibacterial agents . METHODS: The synthetic method reported in literature has been modified and new 3,5-disubstituted oxazolidinone compounds were synthesized on the basis of SAR reported in the literature and their antibacterial activities in vitro were determined . RESULTS: Eighteen new objective compounds were synthesized, and their structures were determined by IR, 1HNMR and FAB-MS . Within the eighteen new objective compounds, sixteen compounds showed antibacterial activity in vitro and compound 9, 10 and 10b showed better antibacterial activities in vitro than ciprofloxacin (CIP), sultamicillin (Sul) and vancomycin (VCO) . Compounds 9a and 11c have no antibacterial activity in vitro at all . CONCLUSION: Compounds 9, 10 and 10b are worthy to be intensively studied.

Biosci Biotechnol Biochem, 2003 Dec, 67(12), 2614 - 20
Pyrazolecarboxylic acid derivative induces systemic acquired resistance in tobacco; Yasuda M et al.; Systemic acquired resistance (SAR) is a potent innate immunity system in plants that is induced through asalicylic acid (SA)-mediated pathway . Here, we characterized 3-chloro-1-methyl-1H-pyrazole-5-carboxylic acid (CMPA) as an effective SAR inducer in tobacco . Soil drench application of CMPA induced PR gene expression and a broad range of disease resistance without antibacterial activity in tobacco . Both analysis of CMPA's effects on NahG transgenic tobacco plants and SA measurement in wild-type plants indicated that CMPA-induced resistance enhancement does not require SA . Therefore, it is suggested that CMPA induces SAR by triggering the signaling at the same level as or downstream of SA accumulation as do both benzo(1,2,3)thiadiazole-7-carbothioic acid S-methyl ester and N-cyanomethyl-2-chloroisonicotinamide.

J Antimicrob Chemother, 2004 Feb, 53(2), 149 - 57 Epub 2004 Jan 16.
Tissue kinetics of telithromycin, the first ketolide antibacterial; Muller-Serieys C et al.; The potential efficacy of an antibacterial depends not only on its spectrum of activity but also on its concentration at the site of infection . The tissue kinetics of telithromycin-the first ketolide antibacterial-are reviewed here . Telithromycin accumulates rapidly in white blood cells, inflammatory fluid, and cells and tissues of the upper and lower respiratory tract, with mean concentrations above the MICs of key respiratory pathogens . Tissue kinetics of telithromycin support facilitated delivery to the site of infection, good efficacy against intracellular respiratory pathogens and respiratory pathogens at extracellular sites in the airways, and effectiveness in the treatment of upper and lower respiratory tract infections (RTIs) . The tissue kinetics profile of telithromycin, together with its microbiological profile, makes it a promising new antibacterial for the treatment of community-acquired RTIs.

Chem Res Toxicol, 2004 Jan, 17(1), 55 - 62
Cytotoxic action of juglone and plumbagin: a mechanistic study using HaCaT keratinocytes; Inbaraj JJ et al.; Juglone (5-hydroxy-1,4-naphthoquinone) and plumbagin (5-hydroxy-3-methyl-1,4-naphthoquinone) are yellow pigments found in black walnut (Juglans regia) . Herbal preparations derived from black walnut have been used as hair dyes and skin colorants in addition to being applied topically for the treatment of acne, inflammatory diseases, ringworm, and fungal, bacterial, or viral infections . We have studied the cytotoxicity of these quinones to HaCaT keratinocytes . Exposure to juglone or plumbagin (1-20 microM) resulted in a concentration-dependent decrease in cell viability . The cytotoxicity of these quinones is due to two different mechanisms, namely, redox cycling and reaction with glutathione (GSH) . Redox cycling results in the generation of the corresponding semiquinone radicals, which were detected by electron paramagnetic resonance . Incubation of keratinocytes with the quinones generated hydrogen peroxide (H(2)O(2)) and resulted in the oxidation of GSH to GSSG . Depletion of GSH by buthionine sulfoximine enhanced semiquinone radical production, increased H(2)O(2) generation, and produced greater cytotoxicity, suggesting that GSH plays an important protective role . Both quinones decreased the intracellular levels of GSH . However, plumbagin stoichiometrically converted GSH to GSSG, indicating that redox cycling is its main metabolic pathway . In contrast, much of the GSH lost during juglone exposure, especially at the higher concentrations (10 and 20 microM), did not appear as GSSG, suggesting that the cytotoxicity of this quinone may also involve nucleophilic addition to GSH . Our findings indicate that topical preparations containing juglone and plumbagin should be used with care as their use may damage the skin . However, it is probable that the antifungal, antiviral, and antibacterial properties of these quinones are the result of redox cycling.

AAPS PharmSciTech . 2000 Mar 03;1(1):E2.
Liposome-based formulations for the antibiotic nonapeptide Leucinostatin A: Fourier transform infrared spectroscopy characterization and in vivo toxicologic study; Ricci M et al.; Leucinostatin-A is a nonapeptide isolated from Paecilomyces marquandii, Paecilomyces lilacinus A257, and Acremonium sp., exerting remarkable phytotoxic, antibacterial (especially against Gram-positive) and antimycotic activities . With the aim to find alternative formulation for in vivo administration, a number of Leucinostatin-A-loaded liposomal formulations have been prepared and characterized . Both large unilamellar vesicles and multilamellar vesicles consisting of synthetic and natural lipids were evaluated . In addition, to determine the nature of peptide-membrane interactions and the stability of liposomes loaded with Leucinostatin-A, a Fourier Transform Infrared Spectroscopy study was performed . The results suggest that the mode of interaction of the peptide is dependent on its concentration, on bilayer fluidity, and on liposome type . Finally, the LD50 of both free and liposome-delivered Leucinostatin-A was determined in mice . These results suggest that the incorporation of Leucinostatin-A into liposomes may result in decreased Leucinostatin-A toxicity, as the intraperitoneal administration of Leucinostatin-A-loaded liposomes reduced the LD50 of Leucinostatin-A 15-fold.

J Org Chem, 2004 Jan 23, 69(2), 387 - 90
An efficient and highly stereocontrolled route to bulgecinine hydrochloride; Khalaf JK et al.; (-)-Bulgecinine is a nonproteinogenic amino acid component present in bulgecins A, B, and C, antibiotic glycopeptides derived from Pseudomonas acidophila and Pseudomonas mesoacidophila . In combination with beta-lactam antibiotics, bulgecins exihibit a unique synergistic antibacterial activity against various Gram-negative microorganisms . Utilizing d-serine as a chiral template and employing a highly regio- and stereoselective intramolecular amidomercuration-oxidation protocol in the key pyrrolidine ring forming step, an efficient total synthetic route to enantiopure bulgecinine is reported herein.

Int Dent J, 2003 Dec, 53(6 Suppl 1), 379 - 84
Plaque antibacterial levels following controlled food intake and use of a toothpaste containing 2% zinc citrate and 0.3% Triclosan; Hall PJ et al.; OBJECTIVES: To measure the levels of zinc and Triclosan present in plaque 12 hours post-brushing and following two weeks home use of a toothpaste formulation containing 2% zinc citrate and 0.3% Triclosan . To measure the levels of zinc and Triclosan in plaque following two weeks home use of the test toothpaste formulation together with a further morning's brushing and a day of controlled food intake . METHODS: A total of 104 subjects completed the study . Plaque samples were taken before use of the test toothpaste and again after a specified regime of product use and food intake . The samples were analysed for zinc or Triclosan . RESULTS: Levels of zinc and Triclosan in plaque 12 hours after last brushing and following a 2-week home usage of product, were 149.1 microg/g and 8.6 microg/g respectively . Following a morning brushing and a day of controlled food intake zinc and Triclosan levels were 94.7 microg/g and 4.1 microg/g respectively . These levels of agents were found to reduce pH drop in vitro . CONCLUSIONS: Regular use of a toothpaste containing 2% zinc citrate and 0.3% Triclosan can lead to a build-up of antibacterial agents in plaque that continue to work even after controlled food intake.

Med Mycol, 2003 Dec, 41(6), 529 - 31
Fungal peritonitis caused by Bipolaris spicifera; Bava AJ et al.; An episode of fungal peritonitis was produced by Bipolaris spicifera in a 3-year-old girl with chronic renal failure secondary to uremic-hemolytic syndrome and who was under treatment with continuous ambulatory peritoneal dialysis (CAPD) . Previously, an episode of purulent peritonitis caused by Pseudomonas spp . had been treated successfully with combined antibacterial therapy for 10 days . Microscopic and macroscopic examinations of the freshly collected purulent dialysate were negative for fungal structures and bacteria . The fungus grew from the dialysate plated on Sabouraud dextrose agar and was also macroscopically recognized as a colony attached to the inner wall of the Tenckhoff catheter . Specific cultures of dialysate for common bacteria and mycobacteria were negative . The patient was successfully treated with early catheter removal and empirical administration of 200 mg/day oral fluconazole for 2 weeks . Subsequently, a new catheter was placed and the patient continued well on CAPD . Post-treatment control cultures of dialysate for fungi, bacteria and mycobacteria were negative and the cell count returned to normal.

Gut, 2004 Feb, 53(2), 246 - 50
Antibiotic use and the development of Crohn's disease; Card T et al.; BACKGROUND: Few environmental determinants of Crohn's disease are well established . Some observational data exist to implicate antibiotic use as a risk factor but these are derived from studies using questionnaires to assess reported antibiotic use that were susceptible to recall bias . We have therefore explored this relationship in prospectively gathered data . METHODS: We selected incident cases of Crohn's disease from the General Practice Research Database with at least five years of data prior to diagnosis . Controls with five years of complete data were randomly selected . Data were extracted on smoking, drug prescriptions, age, sex, and a variety of symptoms and diagnoses that might be indicative of occult Crohn's disease . Logistic regression was used to investigate the relationship between antibiotic use and Crohn's disease . RESULTS: A total of 587 Crohn's disease cases and 1460 controls were available for analysis . We found that antibiotic use 2-5 years pre-diagnosis occurred in 71% of cases compared with 58% of controls (p<0.001), and the median number of courses was two in the cases and one in the controls (p<0.001) . Adjusting for age, sex, smoking, and use of other drugs, antibiotic use had an odds ratio of 1.32 (1.05-1.65) . We were unable to show specificity to any subgroup of antibacterials . Associations similar to that with antibiotics were also found with oral contraceptive, cardiovascular, and neurological drugs . CONCLUSIONS: We found a statistically significant association between Crohn's disease and prior antibiotic use . This cannot be explained by recall bias, but due to lack of specificity it is unclear whether it is causal.

Lik Sprava, 2003 Oct-Nov, (7), 70 - 3
{Modern principals of antibacterial therapy of suppurative-septic diseases}; Okhunov AO et al.; The carried out researches concerning initial nidus of infection have shown a high rate of anaerobic infection especially in patients with destructive-suppurative lung disease, liver abscess, peritonitis (up to 82.8%) . An aerobic-anaerobic association of microbes remarkably often is found in the nidus of infection . We recommend the following preventive scheme to treat patients with different pyoseptic diseases . The scheme is based on the results of our 10 years experience treatment of such patients . It consists of a combination of 2.0 gr . cefoperazoli twice daily, metronidasoli 500 mg . 3 times and amycacini 500 mg twice daily . The intra-arterial or intravenous introduction of the medications was possibly preferred . Having analyzed the results of the treatment of 13,747 patients treated at the center of contaminated surgery, we would note that in 30.2% of the cases were reached excellent results . The above-mentioned scheme of antibacterial therapy with surgical correction of suppurative focus allowed us to reach good results in 45.4% . The satisfactory results of the treatment were achieved in 22.8% of patients . Mortality rate was up to 1.9%.

Am J Respir Med, 2002, 1(2), 147 - 52
Spotlight on zanamivir in influenza; Cheer SM et al.; Zanamivir is a potent competitive inhibitor of the neuraminidase glycoprotein, which is essential in the infective cycle of influenza A and B viruses . Zanamivir (10 mg by inhalation via the Diskhaler twice daily, or 10 mg inhaled plus 6.4 mg intranasally 2 or 4 times daily, for 5 days) reduced the median time to alleviation of major influenza symptoms by up to 2.5 days compared with placebo . Significant reductions of 1 to 2.5 days versus placebo were observed with inhaled zanamivir in phase III trials involving otherwise healthy adults, high-risk patients or children aged 5 to 12 years . Accelerated return to normal activities, and reduced interference with sleep, consumption of relief medication and incidence of complications leading to antibacterial use were also observed with zanamivir . When used for prophylaxis, inhaled zanamivir 10 to 20 mg/day for 10 days to 4 weeks (plus 6.4 mg/day intranasally in one trial) prevented influenza A in 67% of recipients in a university community, significantly reduced the number of families with new cases of influenza compared with placebo or prevented new cases of influenza in long-term care facilities . The tolerability of inhaled or intranasal zanamivir was similar to that of placebo in otherwise healthy adults, high-risk and elderly patients, and children . Recommended dosages of zanamivir did not adversely affect pulmonary function in patients with respiratory disorders in a well-controlled trial, although there have been rare reports of bronchospasm and/or a decline in respiratory function . In conclusion, zanamivir (used within 48 hours of symptom development) reduces the duration of symptomatic illness, causes accelerated return to normal activities or reduces complications requiring antibacterial use in adults, high-risk individuals and children with influenza . Vaccination remains the intervention of choice for prophylaxis in selected populations . However, the efficacy, good tolerability profile and lack of resistance with zanamivir make it a useful option, particularly in those not covered or inadequately protected by vaccination, who are able to use the inhalation device . The use of zanamivir in patients with respiratory disorders remains unclear because of concerns regarding its potential for bronchospasm . Prospective cost-effectiveness analyses and investigations of efficacy in preventing serious complications of influenza, particularly in high-risk patients, are required . Zanamivir shows potential for prophylaxis in persons for whom vaccination is contraindicated or ineffective, in elderly or high-risk patients in long-term care facilities and in households.

Am J Respir Med, 2002, 1(3), 201 - 9
Intrapulmonary pharmacokinetics of antibacterial agents: implications for therapeutics; Chiu LM et al.; The idea of studying the pharmacokinetics and pharmacodynamics of antibacterials in order to predict their efficacy has long been of interest . Traditionally, serum drug concentrations have been evaluated against the minimum inhibitory concentration (MIC) of a given pathogen; however, infection site-specific data continue to gain interest from clinicians . Despite methodological limitations, progress in techniques has improved the clinical significance of data generated . Rather than using tissue homogenates which fail to differentiate between interstitial and intracellular concentrations, newer collection techniques focus on sampling of matrices that allow for this differentiation . These collection techniques now allow one to accurately describe beta-lactam and aminoglycoside interstitial penetrations, as well as, the interstitial and phagocytic concentrations of macrolides and fluoroquinolones . By using these specific data and the MICs of infecting pathogens, it is hoped that conclusions can be drawn by a clinician as to the appropriateness of the choice of an antibacterial.

Am J Respir Med, 2002, 1(5), 339 - 47
Changing paradigms in the diagnosis and management of bronchiectasis; Greenstone M; The face of bronchiectasis may have changed in recent years but individual cases continue to pose difficult challenges . As childhood infection becomes less of a problem, alternative causes of bronchiectasis are increasingly recognized which themselves offer new problems of diagnosis and management . Evolving concepts of pathogenesis suggest alternative strategies for treatment but as yet the evidence base on which to make firm decisions is lacking . Antibacterial regimens are not universally applicable and individualized protocols with parenteral, nebulized or continuous antibacterial therapy are increasingly used in the treatment of patients with bronchiectasis . Despite the theoretical appeal of using mucolytic or anti-inflammatory drugs their roles are still uncertain and have yet to be examined in adequate clinical trials . The factors determining disease progression are still poorly understood but in some patients worsening airflow obstruction heralds the onset of ventilatory failure . The management of the latter requires bronchodilators and controlled oxygen therapy, and strategies including non-invasive ventilation are increasingly an option . Changing indications for surgery are evident with fewer palliative resections but a developing role for transplantation.

Am J Respir Med, 2003, 2(5), 367 - 70
Preventing exacerbations of chronic bronchitis and COPD: therapeutic potential of mucolytic agents; Poole PJ et al.; It is important to find interventions that will reduce the frequency and severity of exacerbations of COPD, because of their effect on morbidity and healthcare expenditure . A Cochrane systematic review included 23 studies that had evaluated the effects of treatment with mucolytic agents in patients with chronic bronchitis or COPD . Mucolytic treatment was associated with a significant reduction of 0.79 exacerbations per patient per year compared with placebo, a 29% decrease . Patients who received treatment with mucolytic agents were twice as likely to remain exacerbation-free in the study period than if they had received placebo, with six patients needing regular treatment with mucolytic agents for 3-6 months to achieve one less exacerbation over that time . Treatment with mucolytic agents resulted in nearly 7 days less illness per patient per year.How mucolytic agents work is unknown, although they may reduce exacerbations by altering mucus production, antioxidation, or antibacterial or immunostimulatory effects . They do not appear to affect the decline in lung function that occurs in COPD . The treatment appears to be without any adverse effects, apart from the need to take oral medication daily . Cost-effectiveness analysis suggests that the point at which the costs of treatment and non-treatment were equal was 1.2 less exacerbations per year . This is higher than the effect observed in the Cochrane review, suggesting that treating everyone with COPD with mucolytic agents would not be cost effective . Those with more frequent and severe exacerbations appear to have the most to gain.

Eur Cytokine Netw, 2003 Oct-Dec, 14(4), 242 - 5
Interleukin-1 receptor antagonist transiently impairs antibacterial defense but not survival in murine pneumococcal pneumonia; Rijneveld AW et al.; The inhibition of the biological activity of IL-1 by recombinant human IL-1 receptor antagonist (IL-1ra) has been investigated in several, controlled clinical trials . Encouraging results have been reported, in particular in patients with rheumatoid arthritis . In the present study, we investigated the influence of treatment of wild type mice with IL-1ra, which resulted in an incomplete and transient inhibition of IL-1 activity . Treatment with recombinant human IL-1ra resulted in an enhanced bacterial outgrowth in the lungs of BALB/c and C57BL/6 mice early after induction of pneumococcal pneumonia, without influencing survival or the pulmonary inflammatory response . The effect of IL-1ra on the host response to S . pneumoniae pneumonia is modest and transient . The present data, together with the findings in IL-1R*/* mice in earlier work, suggest that IL-1 occupies a role in the pulmonary immune response to S . pneumoniae that is substantially less prominent than that of TNF-alpha . Copyright John Libbey Eurotext 2003.

Eur Biophys J, 2004 Aug, 33(5), 448 - 53 Epub 2004 Jan 09.
Location and orientation of Triclosan in phospholipid model membranes; Guillen J et al.; Triclosan is a hydrophobic antibacterial agent used in dermatological preparations and oral hygiene products . Although the molecular mechanism of action of this molecule has been attributed to inhibition of fatty acid biosynthesis, earlier work in our laboratories strongly suggested that the antibacterial action of Triclosan is mediated at least partly through its membranotropic effects . In order to assess its location in phospholipid membranes, high-resolution magic-angle spinning natural abundance (13)C NMR of Triclosan embedded within egg yolk lecithin model membranes has been used to obtain (13)C spin-lattice relaxation times for both Triclosan and lecithin carbon atoms in the presence of Gd(3+ )ions . The results indicate that Triclosan is localized in the upper region of the phospholipid membrane, its hydroxyl group residing in the vicinity of the C = O/C2 carbon atoms of the acyl chain of the phospholipid, and the rest of the Triclosan molecule is probably aligned in a nearly perpendicular orientation with respect to the phospholipid molecule . Intercalation of Triclosan into bacterial cell membranes likely compromises the functional integrity of those membranes, thereby accounting for at least some of this compound's antibacterial effects.

J Biomol Screen, 2003 Dec, 8(6), 712 - 5
The effect of triton concentration on the activity of undecaprenyl pyrophosphate synthase inhibitors; Li H et al.; Undecaprenyl pyrophosphate synthase (UPPS) catalyzes the consecutive condensation of 8 molecules of isopentenyl pyrophosphate with farnesyl pyrophosphate to yield C55-undecaprenyl pyrophosphate, which is required for bacterial cell wall synthesis . UPPS is found in both gram-positive and gram-negative bacteria, and based on the differences between bacterial variants of UPPS and their human counterpart, dolicopyrophosphate synthase, it was identified as an attractive antibacterial target . An assay, which monitors the release of Pi by coupling the UPPS catalyzed reaction with inorganic pyrophosphatase, was employed to conduct an HTS campaign using an inhouse collection of compounds . A direct assay measuring the incorporation of 14C-IPP (isopentenyl pyrophosphate) was used as a secondary assay to evaluate the high-throughput screening (HTS) hits . From the HTS campaign, a few classes of UPPS inhibitors were identified . During the process of hit evaluation by the direct assay, the authors observed that Triton, an essential factor for the enzyme activity and accurate formation of the natural product, dramatically altered the inhibitory activity of a particular class of compounds . Above its critical micellar concentration (CMC), Triton abolished the inhibitory activity of these compounds . Further research will be required to establish the biophysical phenomenon that causes this effect . Meanwhile, it can be speculated that Triton (and other detergents) above CMC may hinder the identification in screening compounds of certain classes of hits.

Infect Dis Clin North Am, 2003 Sep, 17(3), 635 - 49
Clinical pharmacodynamics of antifungals; Andes D; Application of pharmacodynamic principles to antifungal drugs has provided an understanding of the relationship between drug dosing and treatment outcomes similar to that observed in antibacterial pharmacodynamics . Initial observations with triazole pharmacodynamics have correlated with clinical trial results and proved useful for validation of in vitro susceptibility breakpoints . Pharmacodynamic studies have been invaluable for clinical trial dosing design for numerous antibacterial drugs in the development stage . More recently, pharmacodynamics has been used for the development of treatment guidelines . Although there remain many unanswered questions regarding antifungal pharmacodynamics, available data suggest usefulness in the application of pharmacodynamics to antifungal clinical development.

J Biol Chem, 2004 Mar 26, 279(13), 12277 - 85 Epub 2004 Jan 06.
A new group of antifungal and antibacterial lipopeptides derived from non-membrane active peptides conjugated to palmitic acid; Avrahami D et al.; We report on the synthesis, biological function, and a plausible mode of action of a new group of lipopeptides with potent antifungal and antibacterial activities . These lipopeptides are derived from positively charged peptides containing d- and l-amino acids (diastereomers) that are palmitoylated (PA) at their N terminus . The peptides investigated have the sequence K(4)X(7)W, where X designates Gly, Ala, Val, or Leu (designated d-X peptides) . The data revealed that PA-d-G and PA-d-A gained potent antibacterial and antifungal activity despite the fact that both parental peptides were completely devoid of any activity toward microorganisms and model phospholipid membranes . In contrast, PA-d-L lost the potent antibacterial activity of the parental peptide but gained and preserved partial antifungal activity . Interestingly, both d-V and its palmitoylated analog were inactive toward bacteria, and only the palmitoylated peptide was highly potent toward yeast . Both PA-d-L and PA-d-V lipopeptides were also endowed with hemolytic activity . Mode of action studies were performed by using tryptophan fluorescence and attenuated total reflectance Fourier transform infrared and circular dichroism spectroscopy as well as transmembrane depolarization assays with bacteria and fungi . The data suggest that the lipopeptides act by increasing the permeability of the cell membrane and that differences in their potency and target specificity are the result of differences in their oligomeric state and ability to dissociate and insert into the cytoplasmic membrane . These results provide insight regarding a new approach of modulating hydrophobicity and the self-assembly of non-membrane interacting peptides in order to endow them with both antibacterial and antifungal activities urgently needed to combat bacterial and fungal infections.

Ter Arkh, 2003, 75(11), 61 - 4
{Content of the antigenic determinants CD16, CD25, CD95, and HLA-DR in induced sputum of patients with bronchial asthma and chronic obstructive bronchitis}; Nevzorova VA et al.; AIM: To examine the content of CD16, CD25, CD95, and HLA-DR antigenic determinants in induced sputum (IS) of patients with bronchial asthma (BA) and chronic obstructive bronchitis (COB) . MATERIALS AND METHODS: The study enrolled 36 patients with BA and 15 with COB whose age was 21 to 58 years . The cellular precipitate of IS served as a material for the study . The studied receptors were determined by immunofluorescence using the "Clonospectrum" monoclonal antibodies . RESULTS: There was an increase in the content of CD16, CD25, HLA-DR, CD95 whose expression was decreased when glucocorticosteroids were used . At remission of asthma, the level of these receptors approximated that in the control group . On an exacerbation of COB, the content of these markers was significantly less than that in the controls and the use of antibacterial agents and methylxanthines led to its rise . At remission of COB, CD16 and CD25 cells were not recorded . CONCLUSION: The levels of membrane markers in IM of patients with BA and COB depend on the period of the disease and used therapy.

Proc Natl Acad Sci U S A, 2004 Jan 13, 101(2), 470 - 5 Epub 2004 Jan 05.
A proteomic approach for the analysis of instantly released wound and immune proteins in Drosophila melanogaster hemolymph; Vierstraete E et al.; Insects respond to microbial infection by the rapid and transient expression of several genes encoding antibacterial peptides . In this paper we describe a powerful technique, two-dimensional difference gel electrophoresis, that, when combined with mass spectrometry, can be used to study the immune response of Drosophila melanogaster at the protein level . By comparatively analyzing the hemolymph proteome of 2,000 third-instar Drosophila larvae, we identified 10 differential proteins that appear in the fruit fly hemolymph very early after an immune-challenge with lipopolysaccharides . These proteins can be assigned to the immune response, because they are not induced after sterile injury . Reduction of integral variability or quantification problems related to conventional two-dimensional electrophoresis and improvement of image analysis were achieved by the use of two fluorescent dyes to label the two different protein samples . Some of the immune-induced proteins, such as thioester-containing protein 2, can be assigned to specific aspects of the immune response; others were already reported as being involved in stress response . An immune-induced protein (CG18594) is homologous to a mammalian serine protease inhibitor that mediates the mitogen-activated protein kinase and the NF-kappa B signaling pathways . In addition, a number of proteins that had not been associated with the immune response before were isolated and identified, and some of these were still present in the hemolymph 4 h after injury . Determining the function of all of these immune-induced proteins represents an exciting challenge for increasing our knowledge of insect immunity.

Genome Res, 2004 Jan, 14(1), 90 - 8
Identification of antibiotic stress-inducible promoters: a systematic approach to novel pathway-specific reporter assays for antibacterial drug discovery; Fischer HP et al.; As present antibiotics therapy becomes increasingly ineffectual, new technologies are required to identify and develop novel classes of antibacterial agents . An attractive alternative to the classical target-based approach is the use of promoter-inducible reporter assays for high-throughput screening . The wide usage of these assays is, however, limited by the small number of specifically responding promoters that are known at present . This work describes a novel approach for identifying genetic regulators that are suitable for the design of pathway-specific assays . The basis for the proposed strategy is a large set of antibiotics-triggered expression profiles ("Reference Compendium") . Pattern recognition algorithms applied to the expression data pinpoint the relevant transcription-factor-binding sites in whole-genome sequences . Using this technique, we constructed a fatty-acid-pathway-specific reporter assay that is based on a novel stress-inducible promoter . In a proof-of-principle experiment, this assay was shown to enable screening for new small-molecule inhibitors of bacterial growth.

Org Lett, 2004 Jan 8, 6(1), 63 - 6
Peptide quinoline conjugates: a new class of RNA-binding molecules; Krishnamurthy M et al.; {reaction: see text} A synthesis of 4,8-disubstituted 2-phenylquinoline amino acids is reported with the incorporation of one example into a peptide by solid-phase synthesis . The phenylquinoline-containing peptide binds an RNA target with nanomolar affinity (K(D) = 208 nM) . The strategy can be used to prepare a variety of 2-substituted quinoline amino acids for alteration of affinity in intercalator peptides . Since quinolones represent an important class of antibacterials, these compounds may be useful in the discovery of new antibacterial agents.

Cornea, 2004 Jan, 23(1), 38 - 42
Clinical and epidemiological advantages of culturing bacterial keratitis; Wilhelmus KR et al.; PURPOSE: To examine how the corneal culture result is associated with the antibacterial treatment response rate of ulcerative keratitis in a prospective cohort study and to determine whether culture confirmation affects the relative treatment effect in randomized clinical trials of bacterial keratitis . METHODS: The influence of a positive bacterial culture on the rates of antibacterial improvement and cure was estimated by proportional hazards regression among 608 patients with ulcerative keratitis treated with topical ciprofloxacin monotherapy . The interaction of culture confirmation on the relative cure rates of 735 patients enrolled in 4 clinical trials comparing fluoroquinolone monotherapy to combined cephalosporin and aminoglycoside therapy was evaluated by metaregression . RESULTS: In a prospective cohort study, bacterial keratitis that was culture positive and longer than 4 mm had a 37% (95% confidence interval, 20%, 51%) slower improvement rate and a 56% (95% confidence interval, 41%, 67%) slower cure rate during ciprofloxacin therapy . Among randomized clinical trials, the culture result did not modify the relative effect of treatments having similar 1-week cure rates . CONCLUSIONS: Culture confirmation affects the antibacterial therapeutic response rate of ulcerative keratitis and, while not modifying the comparative effect of equivalent antibacterial treatments, facilitates generalizability of clinical trials of bacterial keratitis.

Br J Community Nurs, 2003 Dec, 8(12), S14 - 20
The use of honey for the treatment of two patients with pressure ulcers; Van der Weyden EA; Chronic wounds such as pressure ulcers, leg ulcers and diabetic wounds are a common problem among older people and alternative methods to the current time-consuming and costly practices of wound management in the nursing home need to be identified . To this end, we trialled the use of a honey alginate on two elderly males in our nursing home who were suffering from pressure ulcers (one on the ankle and one on the sacral region), to evaluate its effectiveness as a viable alternative to the current wound management practices in nursing homes . The use of honey resulted in a rapid and complete healing of both wounds . In addition, the antibacterial activity of honey had a deodorizing effect on the wounds and its anti-inflammatory actions helped reduce the level of pain . Similar healing results are also being observed in other patients with pressure-induced ulcers and as a result honey alginates are now being used as the 'standard' treatment for chronic wounds in our nursing home.

Carbohydr Res, 2004 Jan 22, 339(2), 385 - 92
Synthesis and evaluation of a mechanism-based inhibitor of KDO8P synthase; Belakhov V et al.; The enzyme 3-deoxy-D-manno-2-octulosonate-8-phosphate (KDO8P) synthase catalyzes the condensation reaction between phosphoenolpyruvate (PEP) and D-arabinose 5-phosphate (A5P) to produce KDO8P and inorganic phosphate . In attempts to investigate the lack of antibacterial activity of the most potent inhibitor of KDO8P synthase, the amino phosphonophosphate 3, we have synthesized its hydrolytically stable isosteric phosphonate analogue 4 and tested it as an inhibitor of the enzyme . The synthesis of 4 was accomplished in a one step procedure by employing the direct reductive amination in aqueous media between unprotected sugar phosphonate and glyphosate . The analogue 4 proved to be a competitive inhibitor of KDO8P synthase with respect to both substrates A5P and PEP binding . In vitro antibacterial tests against a series of different Gram-negative organisms establish that both inhibitors (3 and 4) lack antibacterial activity probably due to their reduced ability to penetrate the bacterial cell membrane.

Mol Immunol, 2004 Feb, 40(12), 877 - 86
Peptidoglycan recognition proteins (PGRPs); Dziarski R; Innate immune system recognizes microorganisms through a series of pattern recognition receptors that are highly conserved in evolution . Peptidoglycan recognition proteins (PGRPs) are pattern recognition molecules that are conserved from insects to mammals and recognize bacteria and their unique cell wall component, peptidoglycan (PGN) . Drosophila, mosquito, and mammals have families of 13, 7, and 4 PGRP genes, respectively, and some of these genes are alternatively spliced . PGRPs are differentially expressed in various cells and tissues, their expression is often upregulated by bacteria, and they mediate host responses to bacterial infections . Insect PGRPs have four known effector functions that are unique for insects: activation of prophenoloxidase cascade, activation of Toll receptor, activation of Imd pathway, and induction of phagocytosis . One function, amidase activity, is shared by some insect and mammalian PGRPs, whereas antibacterial activity of some mammalian PGRPs is unique for mammals.

Bioorg Med Chem Lett, 2004 Jan 19, 14(2), 393 - 5
Synthesis and antibacterial activity of 7-(substituted)aminomethyl quinolones; Zhang Z et al.; A series of 7-(substituted)aminomethyl quinolones was synthesized and evaluated for antibacterial activity . Derivatives with (monoalkyl)aminomethyl substituent at C-7 displayed high in vitro activities comparable to Lomefloxacin against gram-negative organisms, whereas those bearing a {(substituted)phenyl}aminomethyl side chain at C-7 demonstrated good activities against gram-positive organisms as potent as Lomefloxacin and Vancomycin.

J Colloid Interface Sci, 2004 Feb 15, 270(2), 315 - 20
Avidin self-associates with boric acid gel suspensions: an affinity boron carrier that might be developed for boron neutron-capture therapy; Bench BJ et al.; It has been shown in preliminary studies that the antibacterial protein avidin self-associates with the boric acid gel polymer, and avidin-coated gel particles in the micrometer and submicrometer size ranges are of interest for boron neutron-capture therapy (BNCT), which is neutron-induced fission of boron-10 to produce intense alpha radiation for tumor destruction . The gel particles carry large amounts of boron-10 and are theoretically able effect a meaningful tissue dosing through BNCT . A gross precipitation of gel particles occurs within 46 min of mixing when the avidin/colloid ratio is about 0.34 g avidin/g colloid . This is a minimum time if gel and avidin concentrations are in the low microgram/milliliter range, but at higher proportions of avidin the time delay to precipitation increases significantly; i.e., the colloid surface becomes blocked, inhibiting lattice formation . The avidin-coated gel particles eventually cross-link, forming a solid matrix and precipitating on a timescale measured on the order of an hour . At shorter exposure times rapid agglutination-like reactions were observed with biotinylated bovine albumin, suggesting that two-stage pretargeting of specific tissues should be possible with biotinylated antitumor antibodies . However, for BNCT to be practical, avidin's interaction with the gel needs to be strengthened, and all aryl-B(OH)(2) groups on the particle surfaces must be blocked, or else the particles will interact strongly and nonspecifically with each other and with the carbohydrate groups present on most cell surfaces . Glyceric acid delays the precipitation of the particle suspensions while most simple and complex carbohydrates accelerate it.

J Exp Ther Oncol, 2003 Sep-Oct, 3(5), 283 - 88
Antitumor effect of stilbenoids from Vateria indica against allografted sarcoma S-180 in animal model; Mishima S et al.; Dipterocarpaceous plants contain various resveratrol oligomers that exhibit a variety of biological activities, such as antibacterial and antitumor effects . Previously, we found that vaticanol C, a resveratrol tetramer, exhibits strong cytotoxicity against various tumor cell lines . In the present study, we examined the antitumor activity of the ethanol extract from the stem bark of Vateria indica, which has been traditionally used for health and healing diseases as Ayurveda in India . High-performance liquid chromatography analysis showed that the extract contains bergenin, hopeaphenol, vaticanol B, vaticanol C, and epsilon-viniferin . The in vitro assay displayed the extract's anti-cancer activity against mouse sarcoma 180 cells (IC50=29.5 microM) . In the animal study, the tumor growth of sarcoma S-180 cells subcutaneously allografted in DDY mice was significantly retarded by oral administration of the extract (30 or 100 mg/kg body weight: P < 0.001) . The extract did not show significant toxicity to mice even at a dosage of 1000 mg/kg body weight by daily oral administration for 28 days . These results demonstrated that the ethanol extract containing various stilbenoids from the stem bark of V . indica has the potent antitumor activity.

Antimicrob Agents Chemother, 2004 Jan, 48(1), 30 - 40
High-throughput screen for inhibitors of transglycosylase and/or transpeptidase activities of Escherichia coli penicillin binding protein 1b; Chandrakala B et al.; Penicillin binding protein (PBP) 1b of Escherichia coli has both transglycosylase and transpeptidase activities, which are attractive targets for the discovery of new antibacterial agents . A high-throughput assay that detects inhibitors of the PBPs was described previously, but it cannot distinguish them from inhibitors of the MraY, MurG, and lipid pyrophosphorylase . We report on a method that distinguishes inhibitors of both activities of the PBPs from those of the other three enzymes . Radioactive peptidoglycan was synthesized by using E . coli membranes . Following termination of the reaction the products were analyzed in three ways . Wheat germ agglutinin (WGA)-coated scintillation proximity assay (SPA) beads were added to one set, and the same beads together with a detergent were added to a second set . Type A polyethylenimine-coated WGA-coated SPA beads were added to a third set . By comparison of the results of assays run in parallel under the first two conditions, inhibitors of the transpeptidase and transglycosylase could be distinguished from inhibitors of the other enzymes, as the inhibitors of the other enzymes showed similar inhibitory concentrations (IC(50)s) under both conditions but the inhibitors of the PBPs showed insignificant inhibition in the absence of detergent . Furthermore, comparison of the results of assays run under conditions two and three enabled the distinction of transpeptidase inhibitors . Penicillin and other beta-lactams showed insignificant inhibition with type A beads compared with that shown with WGA-coated SPA beads plus detergent . However, inhibitors of the other four enzymes (tunicamycin, nisin, bacitracin, and moenomycin) showed similar IC(50)s under both conditions . We show that the main PBP being measured under these conditions is PBP 1b . This screen can be used to find novel transglycosylase or transpeptidase inhibitors.

Fitoterapia, 2004 Jan, 75(1), 85 - 8
Antibacterial and antifungal activities of Trewia polycarpa roots; Chamundeeswari D et al.; The total alcoholic extract, its chloroform soluble and aqueous fractions of the roots of the plant Trewia polycarpa exhibited varying degrees of antibacterial and antifungal activities when tested with six bacterial and four fungal strains.

Fitoterapia, 2004 Jan, 75(1), 77 - 80
Comparative studies on biological activities of Prunus padus and P . spinosa; Kumarasamy Y et al.; Comparative studies on the antibacterial and free radical scavenging activities of the n-hexane, dichloromethane and methanol extracts of the seeds of Prunus padus and P . spinosa have been carried out . General toxicity of these extracts has also been determined.

Compend Contin Educ Dent, 2003 Sep, 24(9 Suppl), 4 - 9; quiz 42
The technology behind Colgate Total Advanced Fresh; Williams MI et al.; In the early 1990s, a breakthrough toothpaste, Colgate Total, was launched with documented long-lasting activity against plaque, gingivitis, calculus, tooth decay, and bad breath . The technology behind this toothpaste is the combination of triclosan, a polyvinylmethylether/maleic acid copolymer, and sodium fluoride . The copolymer ensures maximal oral retention and subsequent release of the antibacterial triclosan . Effective levels of triclosan have been observed in the oral cavity 12 hours after brushing the teeth, allowing prolonged control of oral bacteria that may cause the most common dental problems, including bad breath . Similarly, the enhanced retention of triclosan to oral surfaces after using this revolutionary toothpaste for up to 2 years has led to significantly reduced incremental coronal caries compared to an American Dental Association-Approved anticavity fluoride toothpaste . Furthermore, significantly less calcium remained in dental plaque after brushing the teeth with the triclosan/copolymer toothpaste, resulting in the formation of less tartar . In keeping with the multiple oral health benefits provided by Colgate Total, consumers are now offered a new dentifrice, Colgate Total Advanced Fresh, which provides the numerous therapeutic and esthetic benefits that are the hallmark of Colgate Total . The new dentifrice, which contains an impactful breath-freshening flavor, has been documented to provide sustained control of bad breath over 12 hours.

Arch Insect Biochem Physiol, 2004 Jan, 55(1), 43 - 8
Immune stimulation in the silkworm, Bombyx mori L., by CpG oligodeoxynucleotides; Kim I et al.; Synthetic ODNs containing unmethylated CpG dinucleotides are known to stimulate immune responses in vertebrates, but so far the effect has not been studied in insects . In this report, we describe an induction of immune response following injection of oligodeoxynucleotides (ODNs) into the insect hemocoel . The fifth instar silkworm (Bombyx mori L.) larvae were injected with several synthetic ODNs containing variable number of unmethylated CpG motifs, heat-denatured genomic DNA of B . mori itself, or intact genomic DNA to observe a new induction pattern in the insect immune mechanism . When the induction of immune response was examined based on the expression rates of genes for antibacterial peptides such as attacin and cecropin, we could confirm that it was triggered upon injection of ODNs . The expression was, however, neither dependent on numbers of CpG motifs nor methylation of CpGs in ODNs . Furthermore, it was confirmed that the presence of CpG in ODN was not involved in the induction pattern of insect immunity caused by ODNs, although it has been reported that vertebrates respond in a specific manner against invading ODNs containing CpG dinucleotides . In addition, insect immunity was not stimulated by injection of intact DNA from host . In contrast, the injection of denatured genomic DNA provoked the host immune reaction . Taken together, our data suggest that foreignness of ODNs or DNA might be a key factor in the induction of insect immunity .

J Mol Model (Online), 2004 Apr, 10(2), 102 - 11 Epub 2003 Dec 23.
Usefulness of graphical invariants in quantitative structure-activity correlations of tuberculostatic drugs of the isonicotinic acid hydrazide type; Bagchi MC et al.; Quantitative structure-activity relationship (QSAR) studies have been performed for a series of 2-substituted isonicotinic acid hydrazides utilizing theoretical molecular descriptors . 223 topological (topostructural and topochemical) indices along with seven geometrical descriptors were computed for the prediction of antibacterial activity against Mycobacterium tuberculosis . Ridge-regression models assessed by cross-validated R(2) have been formulated, and a comparative study on the relative effectiveness of physicochemical vis-a-vis theoretical molecular descriptors performed . The models developed clearly indicate the supremacy of structure-activity over property-activity relationships in the current study and can be used to evaluate the potential tuberculostatic activity of other INH derivatives, real or hypothetical.

J Intern Med, 2004 Jan, 255(1), 125 - 9
Beta-lactamase inhibitor enhances Helicobacter pylori eradication rate; Ojetti V et al.; OBJECTIVES: One-week triple therapy, a combination of acid suppression with two antibiotics, is the gold standard for anti-Helicobacter pylori treatment . There is increasing evidence of H . pylori resistance to classical triple therapy . Recently, it was reported that the amoxicillin-clavulanate combination had a slightly higher activity than amoxicillin alone against H . pylori, and that beta-lactamase inhibitors had 'in-vitro' antibacterial activity against H . pylori . SETTING: To evaluate the efficacy of 1 week triple therapy omeprazole, clarithromycin and amoxicillin plus clavulanate compared with omeprazole, clarithromycin and amoxicillin for H . pylori eradication . The study was open randomized . SUBJECTS: Sixty dyspeptic patients (36 male, 24 female; mean age 53 +/- 9 years) with Helicobacter pylori infection never treated before, were enrolled and randomly assigned to two different 7-day triple therapies: (i) (n = 30) amoxicillin 875 mg plus clavulanic acid 125 mg b.i.d., clarithromycin 500 mg b.i.d., omeprazole 20 mg b.i.d . (ACCO); (ii) (n = 30) amoxicillin 1 g b.i.d., clarithromycin 500 mg b.i.d., omeprazole 20 mg b.i.d . (ACO) . Bacterial eradication was assessed by 13C-urea breath test 4-6 weeks after therapy . Information on gastrointestinal symptoms and antibiotic-related side-effects were recorded using a questionnaire . RESULTS: All patients completed the study . A significantly higher H . pylori eradication rate with ACCO compared with ACO: (26/30) 86.6 vs . (20/30) 66.6%, respectively (P < 0.05) were observed . No major side-effects were reported, whilst 8% patients complained of mild side-effects; no significant differences were noted between the two groups . CONCLUSIONS: Our results suggest that amoxicillin and clavulanate in combination achieve a higher H . pylori eradication rate than amoxicillin alone, without any increase in side-effects . The combination of amoxicillin and clavulanate may represent an alternative therapeutic scheme for the treatment of H . pylori infection.

J Periodontal Res, 2004 Feb, 39(1), 50 - 8
Effects of eight antibacterial agents on cell survival and expression of epithelial-cell- or cell-adhesion-related genes in human gingival epithelial cells; Inoue K et al.; OBJECTIVE AND BACKGROUND: Our previous studies suggest that little adverse effect on the growth of the periodontal ligament would be expected, if tetracycline, minocycline, ofloxacin, roxithromycin, clarithromycin, and azithromycin were topically administered to the periodontal pocket at their MIC90 doses required to inhibit the growth of 90% of periodontopathic bacteria, including Porphyromonas gingivalis, Prevotella intermedia, and Actinobacillus actinomycetemcomitans . In the present study, we investigated the cytocidal effects of eight antibacterial agents on the human gingival epithelial cell line NDUSD-1 . We also used NDUSD-1 cells to examine the effects of these agents on the mRNA and protein expressions of genes associated with the proliferation, differentiation, or cellular adhesion important to the epithelial regeneration of the periodontal attachment . METHODS: The cytocidal effect of the test agents was measured as a decrease in cell survival . To obtain a quantitative measure of the cytocidal effect, the LD50, i.e . the concentration which results in a 50% decrease in cell survival relative to the controls, was extrapolated from the concentration-response curves . The effects of the agents on the mRNA and protein expressions in NDUSD-1 cells were studied by reverse transcription-polymerase chain reaction (RT-PCR) and western blot analyses, respectively . RESULTS: The cytocidal effect increased in a concentration-dependent manner as the concentration of each of the eight test agents increased . The order of the agents according to their cytocidal effects (LD50) was minocycline > tetracycline > enoxacin > clarithromycin > roxythromycin approximately ofloxacin > azithromycin > erythromycin . The cytocidal effects of minocycline, tetracycline, enoxacin, clarithromycin, roxythromycin, ofloxacin, and azithromycin ranged from 1.2 to 23.2 times greater than that of erythromycin . The maximum non-cytocidal concentrations (MNCCs) of these agents for NDUSD-1 cells were: 0.3 microm for minocycline, 1 microm for tetracycline, 3 microm for ofloxacin and erythromycin, 10 microm for enoxacin, clarithromycin, and azithromycin, and 100 microm for roxythromycin . The MNCCs of ofloxacin, azithromycin, clarithromycin, and roxythromycin were greater than their MIC90 concentrations for periodontopathic bacteria described above . The effects on the mRNA and protein expressions of epithelial-cell- or cell-adhesion-related genes were examined in NDUSD-1 cells exposed to clarithromycin, roxythromycin, ofloxacin, and azithromycin at their MNCCs . None of the agents affected the mRNA expressions of five genes: keratinocyte growth factor receptor, keratin 18, integrin beta1, integrin beta4, and laminin 5gamma2 . Clarithromycin and ofloxacin slightly decreased the protein expression of integrin beta4 . Roxythromycin markedly decreased the protein expressions of integrin beta4 and laminin 5gamma2 . Azithromycin had little inhibitory effects on the protein expressions of any of the five genes . CONCLUSIONS: These results suggest that little, if any, adverse effects on growth, differentiation, and adhesion of basal epithelial cells would be expected with topical administration of clarithromycin, ofloxacin or azithromycin to the periodontal pocket at a dose equivalent to the MIC90 . It is important to note, however, that the extrapolation of these findings to in vivo conditions has yet to be undertaken.

Eur J Clin Pharmacol, 2004 Feb, 59(12), 899 - 904 Epub 2003 Dec 19.
Absolute contraindications in relation to potential drug interactions in outpatient prescriptions: analysis of the first five million prescriptions in 1999; Guedon-Moreau L et al.; OBJECTIVES: Adverse drug interactions increase morbidity and mortality . To prevent these, situations leading to adverse prescriptions must be clarified . This study quantifies and analyses prescriptions with potential adverse drug interactions in primary health care in the North of France over a 3-month period . METHODS: All prescriptions administered between 1 January 1999 and 31 March 1999 were analysed to identify potential interactions amongst drugs appearing on the same prescription sheet . The regional French healthcare database was compiled to further classify contraindications . RESULTS: There were 5,358,374 prescriptions administered to 44% of the overall population of the Nord-Pas de Calais area (1,754,372 patients per 3,990,167 general population) . There were 14,390 prescriptions classified as either absolute (26%) or relative contraindications (74%) . Nine drug categories accounted for most of the absolute contraindications: dopaminergic antiparkinsonians, neuroleptic agents, migraine treatments (such as ergot alkaloids, sumatriptan and other triptan derivatives), prokinetic drugs (cisapride), antibacterial drugs (macrolides), antifungals (imidazoles), antiarrhythmics, beta-blockers and analgesics (opioids and floctafenine) . In 54% of patients exposed, the incurred risk was either QT prolongation/Torsade de Pointes or antagonism of dopaminergic antiparkinson agents with dopamine receptor antagonists prescribed as antipsychotic agents . CONCLUSIONS: Among a non-selected population of ambulatory outpatients, the number of quarterly prescriptions with contraindications with potentially harmful drug interactions is 27 in 10,000 prescriptions . This would extrapolate to nearly 200,000 contraindications on same-prescription sheets in France in the first quarter of 1999.

J Pediatr (Rio J), 1998 Jul, 74(Suppl 1), S21 - 30
{Acute and secretory otitis media}; Pereira MB et al.; OBJECTIVE: Otitis media is the most frequently diagnosed infection in the pediatric office . Ninety per cent of the children present at least one episode of otitis media before the fifth birthday . We reviewed the literature in order to update information regarding the current definitions of acute otitis media, recurrent otitis media and otitis media with effusion, analyzing the predisposing factors, microbiology, clinical manifestations, diagnostic criteria and methods of treatment for these entities, and the relationship between otitis media and language development and learning disabilities.DATA SOURCE: Bibliographic review of an eighteen- year period (1980-1998) using Index Medicus and Medline.RESULTS AND CONCLUSIONS: More than 25 million diagnoses per year of middle ear infections are made in the United States, being responsible for rising costs of treatment . The role of many predisposing factors is presently well recognized and we should be capable of defining interventions related to some of them as is the case of early institution of day-care, short duration of breast feeding and difficulties in the identification and treatment of gastroesophageal reflux . Changes in the microbiology of the middle ear infections and the emergence of multiresistant bacteria leads to modifications in antibiotic therapy and the duration of its use . Antibacterial agents should be prescribed only in the presence of a well-defined diagnosis and chemoprophylaxis should be avoided . Recurrent otitis media and otitis media with effusion in infants may be associated to speech disorders and learning disabilities . The development of a conjugated vaccine against S . pneumoniae and the experiments with a vaccine against non-typeable H . influenzae represent a big step in the prevention of infections of the middle ear for the near future.

Stroke, 2004 Jan, 35(1), 2 - 6 Epub 2003 Dec 18.
Preventive antibacterial treatment improves the general medical and neurological outcome in a mouse model of stroke; Meisel C et al.; BACKGROUND AND PURPOSE: Epidemiological studies have demonstrated a high incidence of infections after severe stroke and their prominent role in morbidity and mortality in stroke patients . In a mouse model, it has been shown recently that stroke is coupled with severe and long-lasting immunosuppression, which is responsible for the development of spontaneous systemic infections . Here, we investigated in the same model the effects of preventive antibiotic treatment on survival and functional outcome of experimental stroke . METHODS: Mice were subjected to experimental stroke by occlusion of the middle cerebral artery (MCAO) for 60 minutes . A group of mice received moxifloxacin (6x100 mg/kg body weight every 2 hours over 12 hours) either immediately or 12 hours after MCAO . Control animals received the vector only . Behavior, neurological deficit, fever, survival, and body weight were monitored over 14 days . In a subgroup, infarct volume was measured 4 days after MCAO . Microbiological assessment was based on cultures of lung tissue, blood, and feces of animals 3 days after stroke . For a dose-response study, moxifloxacin was given immediately after MCAO in different doses and at different time points . RESULTS: Microbiological analyses of blood and lung tissue demonstrated high bacterial burden, mainly Escherichia coli, 3 days after stroke . Accordingly, we observed clinical and histological signs of septicemia and pneumonia . Moxifloxacin prevented the development of infections and fever, significantly reduced mortality, and improved neurological outcome . CONCLUSIONS: Preventive antibiotic treatment may be an important new therapeutical approach to improve outcome in patients with severe stroke.

Bioorg Med Chem Lett, 2004 Jan 5, 14(1), 267 - 70
Structure-activity relationships of novel potent MurF inhibitors; Gu YG et al.; A novel class of MurF inhibitors was discovered and structure-activity relationship studies have led to several potent compounds with IC(50)=22 approximately 70 nM . Unfortunately, none of these potent MurF inhibitors exhibited significant antibacterial activity even in the presence of bacterial cell permeabilizers.

Bioorg Med Chem Lett, 2004 Jan 5, 14(1), 235 - 8
Phenyl thiazolyl urea and carbamate derivatives as new inhibitors of bacterial cell-wall biosynthesis; Francisco GD et al.; Over 50 phenyl thiazolyl urea and carbamate derivatives were synthesized for evaluation as new inhibitors of bacterial cell-wall biosynthesis . Many of them demonstrated good activity against MurA and MurB and gram-positive bacteria including MRSA, VRE and PRSP . 3,4-Difluorophenyl 5-cyanothiazolylurea (3p) with clog P of 2.64 demonstrated antibacterial activity against both gram-positive and gram-negative bacteria.

Bioorg Med Chem Lett, 2004 Jan 5, 14(1), 171 - 5
Novel semi-synthetic nocathiacin antibiotics: synthesis and antibacterial activity of bis- and mono-O-alkylated derivatives; Regueiro-Ren A et al.; Several semi-synthetic bis- and mono-O-alkyl nocathiacin derivatives were synthesized and evaluated for antibacterial activity . Mono-O-alkyl N-hydroxyindole analogues 3a-l were prepared by regioselective alkylation . Bis-O-alkyl nocathiacins 4a-f were obtained by treatment with base and excess electrophile . A one-pot protection-alkylation-deprotection strategy was developed for the preparation of mono-O-alkyl hydroxypyridine analogues 5a,b . Most of the bis- and mono-O-alkyl nocathiacins maintained good in vitro activity but showed reduced in vivo efficacy when compared with the natural product . The excellent in vivo activity and improved water solubility of phosphate analogues 3m and 4g suggest their use as potential pro-drugs.

Bioorg Med Chem Lett, 2004 Jan 5, 14(1), 59 - 62
Peptide deformylase inhibitors with activity against respiratory tract pathogens; East SP et al.; A series of analogues of the peptide deformylase (PDF) inhibitor BB-3497 where the P3' amide bond was replaced with a ketone functionality is described . The in vitro antibacterial profiling of these compounds revealed that they demonstrate activity against pathogens associated with respiratory tract infections.

Nucleic Acids Res, 2004 Jan 1, 32 Database issue, D271 - 2
DEG: a database of essential genes; Zhang R et al.; Essential genes are genes that are indispensable to support cellular life . These genes constitute a minimal gene set required for a living cell . We have constructed a Database of Essential Genes (DEG), which contains all the essential genes that are currently available . The functions encoded by essential genes are considered a foundation of life and therefore are likely to be common to all cells . Users can BLAST the query sequences against DEG . If homologous genes are found, it is possible that the queried genes are also essential . Users can search for essential genes by their function or name . Users can also browse and extract all the records in DEG . Essential gene products comprise excellent targets for antibacterial drugs . Analysis of essential genes could help to answer the question of what are the basic functions necessary to support cellular life . DEG is freely accessible from the website http://tubic.tju.edu.cn/deg/.

J Natl Cancer Inst, 2003 Dec 17, 95(24), 1869 - 77
Randomized controlled trial of once- versus thrice-daily tobramycin in febrile neutropenic children undergoing stem cell transplantation; Sung L et al.; BACKGROUND: The benefits of aminoglycoside antibiotics, such as tobramycin, administered as a once-daily dose to manage febrile neutropenia, have been demonstrated in many patient populations . However, toxicity and safety data are lacking for pediatric stem cell transplant recipients, who are at especially high risk for aminoglycoside-related toxicity and infectious morbidity . In particular, the relative nephrotoxicity and efficacy of tobramycin administered as a single daily dose or as three daily doses among this patient population is not known . METHODS: We conducted a randomized, double-blind controlled study of tobramycin dosing among children 18 years or younger who had fever and neutropenia while undergoing stem cell transplantation . From October 2000 through November 2002, 60 children were randomly assigned to receive intravenous tobramycin, as either a single daily dose (n = 29) or every 8 hours (n = 31), in combination with either piperacillin or ceftazidime (intravenous) . Tobramycin doses were adjusted to achieve pharmacokinetic targets . The primary outcome was nephrotoxicity, as represented by the maximal percent increase in serum creatinine concentration throughout the episode of febrile neutropenia relative to the baseline serum creatinine concentration . Efficacy was a secondary outcome and was defined as survival of the episode without modification of the antibacterial regimen . All statistical tests were two-sided . RESULTS: In a modified intent-to-treat analysis, the mean maximal percent increase in serum creatinine concentration was 32% (N = 26) in the once daily dose group and 51% (N = 28) in the every 8 hours dose group (difference = 19%, 95% confidence interval {CI} = 0% to 38%; P =.054) . Among patients evaluable for efficacy, 12 (46%) of 26 patients in the once daily dose group and five (19%) of 27 patients in the every 8 hours dose group survived the episode of febrile neutropenia without requiring antibacterial treatment modification (difference = 27%, 95% CI = 4% to 52%; P =.03) . There was one death in each group . CONCLUSIONS: In febrile neutropenic children undergoing stem cell transplantation, tobramycin may be less nephrotoxic and more efficacious when administered as a once daily dose than when administered every 8 hours.

Arch Pharm (Weinheim), 2003 Dec, 336(12), 567 - 72
Synthesis and antibacterial activity of 1beta-methyl-2-(5-substituted oxadiazolo pyrrolidin-3-yl-thio)carbapenem derivatives; Oh CH et al.; Synthesis of a new series of 1beta-methylcarbapenems with a substituted oxadiazolopyrrolidine moiety is described . Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of the substituent on the oxadiazole ring investigated . In particular, compounds 13a and 13c with ester and carbamoyl substituted oxadiazole moieties showed the most potent antibacterial activity.

Arch Pharm (Weinheim), 2003 Dec, 336(12), 560 - 6
Synthesis and in vitro antibacterial evaluation of novel imidazo{2',1':5,1}-1,2,4-triazolo{4,3-c}-quinazoline derivatives of 5-thioxo-1, 2, 4-triazole, 4-oxothiazolidine, and their open-chain counterparts; Nasr MN et al.; Two novel series of imidazo{2', 1':5, 1}-1, 2, 4-triazolo{4, 3-c}quinazolines bearing 5-thioxo-1, 2, 4-triazoles, 6a-f, and 4-oxothiazolidines, 7a-f, were synthesized from corresponding thiosemicarbazide derivatives, 5a-f . The stepwise methodology applied to the preparation of compounds 5a-f was initiated with reaction of the parent 3-amino-1, 2, 4-triazolo{4, 3-c}quinazolines, 2, with ethyl 2-chloroacetoacetate resulting in annelation of the imidazole ring to give esters, 3a-c . However, hydrazinolysis of these ester derivatives gave the corresponding acid hydrazides, 4a-c, which on reaction with the appropriate alkyl isothiocyanate yielded compounds 5a-f . In turn, compounds 5, were cyclized with potassium hydroxide or with ethyl bromoacetate to give the corresponding thioxotriazoles 6 and oxothiazolidines 7, respectively . All synthesized compounds were screened for their in vitro antibacterial activity against various Gram-positive and Gram-negative bacteria . Some test compounds were found to possess potent antibacterial activities . Compound, 7f, exhibited much higher potency than the reference standard ciprofloxacin, against both types of bacteria, particularly, Gram-positive organisms.

PDA J Pharm Sci Technol, 2003 Mar-Apr, 57(2), 109 - 13
Synthesis and antibacterial evaluation of 4-substituted-2-phenyl-1-p-tolyl-4-thiomethyl-1,3-diazabuta-1,3-dienes: a novel class of antibacterial agents; Bedi P et al.; A series of novel-2-phenyl-1-p-tolyl-4-thiomethyl-1,3-diazabuta-1,3-dienes compounds (5a-5e) possessing morpholino, diethyl amino, pyrrolidino, piperidino and 2-aminopyridino groups respectively at C-4 were prepared by reaction of alpha-aryliminobenzyl isothiocyanates with secondary amines and S-alklyation of the resultant thioureas with aqueous potassium hydroxide . The isothiocyanates were obtained from easily available starting materials . These 1,3-diazabuta-1,3-dienes were obtained in pure form after recrystallization and their structures were established by analytical and spectral data . The synthesized compounds were screened for their antibacterial activity and some of them were found to exhibit significant antibacterial activity.

Am J Dent, 2003 Sep, 16 Spec No, 68A - 72A
Sealing properties of a self-etching primer system to normal caries-affected and caries-infected dentin; Lee KW et al.; PURPOSE: To compare the ability of an experimental antibacterial self-etching primer adhesive system to seal exposure sites in normal, caries-affected and caries-infected human dentin . METHODS: 30 extracted human third molars were used within 1 month of extraction . 10 intact normal teeth comprised the normal group . 20 teeth with occlusal caries that radiographically extended halfway to the pulp were excavated using caries-detector solution (CDS) and a #4 round carbide bur in a slowspeed handpiece . Half of those teeth were fully excavated free of CDS-stained material without exposing the pulp, and were designated as the caries-affected dentin group . The remaining 10 teeth were excavated as close to the pulp as possible without obtaining an exposure, but whose dentin continued to stain red with CDS; this group was designated as the caries-infected dentin group . The remaining dentin thickness in all of the specimens in the other two groups was then reduced to the same extent as the caries-infected group . Direct exposures of the pulp chamber were made with a 1/4 round bur in the normal dentin or a 25 gauge needle in the other two groups . After measuring the fluid flow through the exposure, the sites were then sealed with an experimental antibacterial fluoride-containing self-etching primer adhesive systems (ABF) . Fluid conductance was remeasured every week for 16 weeks . RESULTS: The fluid conductance through the exposure fell 99% in all groups following resin sealing . The seals of normal and caries-affected dentin remained relatively stable over the 16 weeks, while the seals of caries-infected dentin gradually deteriorated, reaching significance at 8 weeks . TEM examination revealed very thin (ca . 0.5 mm) hybrid layers in normal dentin, 3-4 microm thick hybrid layers in caries-affected dentin and 40 microm thick hybrid layers in caries-infected dentin . The tubules of caries-infected dentin were enlarged and filled with bacteria . Resin tags passed around these bacteria in the top 20-40 microm thereby encapsulating them in resin.

Skinmed, 2002 Sep-Oct, 1(1), 33 - 44
Cutaneous reactions to antibacterial agents; Witkowski JA et al.; Antibacterial agents may cause a variety of untoward reactions . Some range from transient, mild erythema to toxic epidermal necrolysis, often resulting in disability and death . Both in vivo and in vitro tests are becoming useful for the diagnosis of the causative agent in drug eruptions . The drug hypersensitivity syndrome may be associated with thyroid abnormalities often occurring months after the drug has been withdrawn . Symmetrical small joint polyarthritis, fever, and malaise may be the presenting findings in a patient with drug-induced lupus erythematosus . Exanthematous drug eruptions without high fever, mucosal involvement, or joint symptoms often resolve without discontinuation of the drug . The differential diagnosis of Stevens-Johnson syndrome and toxic epidermal necrolysis depends on the percentage of epidermal detachment.

J Food Prot, 2003 Dec, 66(12), 2371 - 6
Significance of nonaromatic organic acids in honey; Mato I et al.; Although organic acids represent < 0.5% of honey's constituents, they make important contributions to the organoleptic, physical, and chemical properties of honey . To date, approximately 30 nonaromatic organic acids have been identified in honey, but relatively little attention has been paid to these components . This article reviews the current literature related to the significance of nonaromatic organic acids in honey; it was written with a goal of attracting researchers to study these interesting honey components . Previous research contributions on nonaromatic organic acids in honey may be classified into five main areas: (i) the antibacterial activities of these acids, (ii) the antioxidant activities of these acids, (iii) the use of these acids as possible indicators of incipient fermentation, (iv) the use of these acids for treatment of Varroa infestation, and (v) the use of these acids as factors for the characterization of both botanical and geographical origins of honeys . We conclude that nonaromatic organic acids are of interest for diverse reasons and that there is a particular need for studies regarding their possible antibacterial and antioxidant activities.

J Food Prot, 2003 Dec, 66(12), 2296 - 301
A comparison of hand washing techniques to remove Escherichia coli and caliciviruses under natural or artificial fingernails; Lin CM et al.; Compared with other parts of the hand, the area beneath fingernails harbors the most microorganisms and is most difficult to clean . Artificial fingernails, which are usually long and polished, reportedly harbor higher microbial populations than natural nails . Hence, the efficacy of different hand washing methods for removing microbes from natural and artificial fingernails was evaluated . Strains of nonpathogenic Escherichia coli JM109 and feline calicivirus (FCV) strain F9 were used as bacterial and viral indicators, respectively . Volunteers with artificial or natural nails were artificially contaminated with ground beef containing E . coli JM109 or artificial feces containing FCV . Volunteers washed their hands with tap water, regular liquid soap, antibacterial liquid soap, alcohol-based hand sanitizer gel, regular liquid soap followed by alcohol gel, or regular liquid soap plus a nailbrush . The greatest reduction of inoculated microbial populations was obtained by washing with liquid soap plus a nailbrush, and the least reduction was obtained by rubbing hands with alcohol gel . Lower but not significantly different (P > 0.05) reductions of E . coli and FCV counts were obtained from beneath artificial than from natural fingernails . However, significantly (P < or = 0.05) higher E . coli and FCV counts were recovered from hands with artificial nails than from natural nails before and after hand washing . In addition, microbial cell numbers were correlated with fingernail length, with greater numbers beneath fingernails with longer nails . These results indicate that best practices for fingernail sanitation of food handlers are to maintain short fingernails and scrub fingernails with soap and a nailbrush when washing hands.

Khirurgiia (Mosk), 2003, (11), 20 - 5
{Laser doppler flowmetry for assessment of acute pancreatitis treatment efficacy}; Briskin BS et al.; Microcirculation was studied with laser doppler flowmetry in 226 patients with acute destructive pancreatitis treated with standard detoxication, antiinflammatory, antibacterial and surgical methods . The examination was performed on the unit LAKK-01 (NPP 'Lazma', Russia) by original methods based on the study of microcirculation in biologically active points . Based on analysis of 2500 dopplerograms, criteria of assessment of organic and systemic capillary circulation and also laser doppler flowmetric characteristics of 4 degree microcirculation's insufficiency were developed . The proposed scheme was effectively applied for assessment of each medical procedure and of all curative complex in general.

Acta Crystallogr C, 2003 Dec, 59(Pt 12), o676 - 8 Epub 2003 Nov 08.
Two biologically active thiophene-3-carboxamide derivatives; Vasu et al.; The two title compounds, 2-({(1Z)-{4-(dimethylamino)phenyl}methylene}amino)-4,5-dimethyl-N-(2-methylphenyl)thiophene-3-carboxamide, C(23)H(25)N(3)OS, (I), and 2-({(1E)-{4-(dimethylamino)phenyl}methylene}amino)-N-(4-methylphenyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide,C(25)H(27)N(3)OS, (II), show antibacterial and antifungal activities . The asymmetric unit of (II) contains two crystallographically independent molecules . The o-toluidine ring in (I) lies gauche with respect to the thiophene ring . In (II), the p-toluidine ring is coplanar with the thiophene ring in one molecule, but is tilted from it in the other molecule . Neither structure exhibits any significant intermolecular interactions, but in both, an intramolecular N-H.N hydrogen bond forms a pseudo-six-membered ring, thus locking the molecular conformation and removing conformational flexibility.

Brain Res, 2004 Jan 16, 996(1), 76 - 80
Rifampicin attenuates brain damage in focal ischemia; Yulug B et al.; Rifampicin is an antibacterial agent that is widely used in tuberculosis and leprosy therapy . Interestingly, some experimental studies indicate that rifampicin acts as a hydroxyl radical scavenger and a glucocorticoid receptor activator . In this study, the neuroprotective effect of rifampicin was evaluated after transient and permanent focal cerebral ischemia . Anaesthetized male C57BL/6j mice were submitted to permanent or transient thread occlusion of the middle cerebral artery (MCA) . Reperfusion in transient ischemia was initiated 30 min later by thread retraction . Rifampicin or vehicle were applied intraperitoneally before permanent or immediately after 30 min of transient ischemia . Later, 24 h after permanent or transient ischemia, animals were re-anesthetized and decapitated . Brain injury was evaluated by triphenyltetrazolium chloride staining (TTC), terminal transferase biotinylated-dUTP nick end labeling (TUNEL) and cresyl violet staining . A 20-mg/kg sample of rifampicin showed a significant neuroprotection after cerebral ischemia . The number of TUNEL-positive cells in the striatum, where disseminated tissue injury was observed, was also reduced by application of rifampicin as compared with vehicle-treated animals . The present report shows that administration of rifampicin efficiently reduces brain injury after permanent and transient focal cerebral ischemia in mice.

Probl Tuberk Bolezn Legk, 2003, (10), 24 - 7
{Peptic ulcer is a risk factor in the surgical treatment of pulmonary tuberculosis}; Kobak ME et al.; Peptic ulcer of the stomach and duodenum is the most common (10-18%) concomitant gastrointestinal pathology in phthisiosurgical patients . Treatment of these patients presents a challenge due to a drastic reduction in the efficiency of oral antibacterial therapy resulted from poor tolerability of chemical drugs and to a risk for surgical complications particularly in the early period after lung surgery . In 1996-2002, a total of 495 patients with tuberculosis at various sites were endoscopically studied; peptic ulcer in different phases was detected in 30.9% of the patients . There has been a considerable increase in the incidence of peptic ulcer among phthisiosurgical patients in the past 3 years (up to 16-17% among those undergone lung surgery for tuberculosis) . A package of measures has been developed to reduce the incidence of life-threatening complications due to peptic ulcer in the postoperative period . It is concluded that peptic ulcer is a significant risk factor in phthisiosurgery as a serious contraindication to planned surgery and as a source of postoperative complications.

Microbiol Mol Biol Rev, 2003 Dec, 67(4), 686 - 723
A continuum of anionic charge: structures and functions of D-alanyl-teichoic acids in gram-positive bacteria; Neuhaus FC et al.; Teichoic acids (TAs) are major wall and membrane components of most gram-positive bacteria . With few exceptions, they are polymers of glycerol-phosphate or ribitol-phosphate to which are attached glycosyl and D-alanyl ester residues . Wall TA is attached to peptidoglycan via a linkage unit, whereas lipoteichoic acid is attached to glycolipid intercalated in the membrane . Together with peptidoglycan, these polymers make up a polyanionic matrix that functions in (i) cation homeostasis; (ii) trafficking of ions, nutrients, proteins, and antibiotics; (iii) regulation of autolysins; and (iv) presentation of envelope proteins . The esterification of TAs with D-alanyl esters provides a means of modulating the net anionic charge, determining the cationic binding capacity, and displaying cations in the wall . This review addresses the structures and functions of D-alanyl-TAs, the D-alanylation system encoded by the dlt operon, and the roles of TAs in cell growth . The importance of dlt in the physiology of many organisms is illustrated by the variety of mutant phenotypes . In addition, advances in our understanding of D-alanyl ester function in virulence and host-mediated responses have been made possible through targeted mutagenesis of dlt . Studies of the mechanism of D-alanylation have identified two potential targets of antibacterial action and provided possible screening reactions for designing novel agents targeted to D-alanyl-TA synthesis.

J Agric Food Chem, 2003 Dec 17, 51(26), 7659 - 63
Comparison of physicochemical, binding, and antibacterial properties of chitosans prepared without and with deproteinization process; No HK et al.; Physicochemical, binding, and antibacterial properties of chitosans prepared without and with deproteinization (DP) process (5, 10, 15, and 30 min at 15 psi/121 degrees C) were compared . Chitosan from DP 0 min had comparable nitrogen content, lower degree of deacetylation and solubility, but higher molecular weight and viscosity than chitosans from DP 5-30 min . The latter four chitosans showed differences only in molecular weight . Deproteinization treatment resulted in slightly decreased L values and increased a and b values compared with those of DP 0 min . Chitosan from DP 0 min had comparable water and fat-binding capacity (FBC) except for chitosan from DP 15 min, which had a higher FBC but lower dye-binding capacity than those of the four chitosans from DP 5-30 min . The antibacterial activities of chitosans against seven different bacteria showed that the inhibitory effects varied with the deproteinization time and the particular bacterium.

Pharmazie, 2003 Nov, 58(11), 767 - 75
Pharmacological activities and mechanisms of natural phenylpropanoid glycosides; Pan J et al.; The pharmacological activities and mechanisms of action of natural phenylpropanoid glycosides extracted from a variety of plants are summarized in this review, such as antitumor, antivirus, anti-inflammation, antibacteria, antiartherosclerosis, anti-platelet-aggregation, antihypertension, antifatigue, analgesia, hepatoprotection, immunosuppression, protection of sex and learning behavior, protection of neurodegeneration, reverse transformation of tumor cells, inhibition of telomerase and shortening telomere length in tumor cells, effects on enzymes and cytokines, antioxidation, free radical scavenging and fast repair of oxidative damaged DNA . Molecular modeling is discussed as well as structure-activity relationships.

Curr Opin Biotechnol, 2003 Dec, 14(6), 621 - 6
Antibacterials: are the new entries enough to deal with the emerging resistance problems?
Barrett CT, Barrett JF.
Fifty years of making analogs based on less than ten antibacterial scaffolds has resulted in the development and marketing of over 100 antibacterial agents but, with the exception of the oxazolidinone core, no new scaffolds have emerged in the past 30 years to address emerging resistance problems . As the support for antibacterial research shifts away from large pharmaceutical companies, a wave of biotechnology companies have pursued a diverse choice of targets resulting in several novel classes of agent in late-stage development . Although critical for certain resistance niche needs, these agents are unlikely to provide the solution to the requirement for a major novel scaffold class of antibacterials.

Int J Pediatr Otorhinolaryngol, 2003 Dec, 67 Suppl 1, S225 - 8
Efficacy of cefpodoxime in the prophylaxis of recurrent pharyngotonsillitis; Mora R et al.; BACKGROUND: Recurrent acute pharyngotonsillitis remains a common illness in children and young adults and can lead to serious complications if not treated . cefpodoxime proxetil is a second-generation oral cephalosporin, which shows potent antibacterial activity against both Gram-positive and Gram-negative bacteria and high stability in the presence of beta-lactamases . OBJECTIVE: We aimed to evaluate the efficacy of second-generation cephalosporins in the prophylaxis of recurrent pharyngotonsillitis in children . METHODS: A total of 180 children aged between 4 and 14 years with recurrent pharyngotonsillitis were randomized to receive either cefpodoxime proxetil (100 mg twice a day, 6 days a month for 6 months) or placebo (at the same dosage) . RESULTS AND CONCLUSIONS: Our results show that treatment with cefpodoxime proxetil may be effective in reducing symptoms of recurrent pharyngotonsillitis and preventing recurrences without causing side effects or developing bacterial resistance.

Ceska Slov Farm, 2003 Nov, 52(6), 282 - 90
{Biologically active benzoxazoles}; Vinsova J; This review presents a survey of preparations and biological activities of substituted benzoxazoles . The structural similarity of benzoxazole derivatives with nucleic bases, such as adenine and guanine, probably allows their easy interaction with biopolymers in the living systems . Consequently, these compounds posses a wide range of biological activities . Their preparation includes cyclocondensation reactions and contractions of ortho-fused heterocycles or their photochemical rearrangement . They are being studied predominantly for their antibacterial, antifungal, antiviral, and antitumor activities, and also as insecticides, herbicides, anthelmintics, histamine antagonists, and fluorescent dyes.

Arch Toxicol, 2004 Feb, 78(2), 61 - 7 Epub 2003 Dec 06.
Concentrations of the des-F(6)-quinolone garenoxacin in plasma and joint cartilage of immature rats; Kastner M et al.; Garenoxacin is a des-F(6)-quinolone with a broad antibacterial spectrum, which has previously been shown to exhibit low chondrotoxicity in juvenile dogs compared with several other quinolones . A study was performed to determine whether the low chondrotoxicity observed in immature rats following garenoxacin treatment could be explained by poor penetration into cartilage tissue . Garenoxacin was orally administered to immature (4- to 5-week-old) Wistar rats as a single dose-or as doses given on 5 consecutive days-of 0 (vehicle), 200, 400, and 600 mg/kg ( n=5 per dose level) . Additional groups of rats were orally dosed with 600 mg/kg ofloxacin and ciprofloxacin . One knee joint of each animal (24 h after the last dose) was studied histologically after staining with Toluidine blue . The pharmacokinetics of garenoxacin in plasma (200, 400, and 600 mg/kg) and in knee joint cartilage (200 and 600 mg/kg) was assessed in separate groups of rats ( n=55 per dose level) . Concentrations of garenoxacin in plasma and cartilage were measured using an HPLC method . No signs of chondrotoxicity were observed in the immature rats treated with garenoxacin or ciprofloxacin for 5 days at the doses investigated in this study . However, ofloxacin was found to induce cartilage lesions that were typical of those seen for this quinolone . Systemic exposure to garenoxacin increased as a function of dose . Across dose and study day, mean garenoxacin plasma maximum concentration ( C(max)) and area under the concentration-time curve (AUC(tau)) values were in the range 12-26 mg/l and 33-133 mgxh/l, respectively . Garenoxacin C(max) and AUC were similar on days 1 and 5, within each dose, indicating the absence of accumulation or reduction in the systemic exposure . Values determined for T(max) (0.25-1.0 h) and T(1/2) (3.8-6.4 h) of garenoxacin in plasma did not vary with dose or study day . Although peak garenoxacin concentrations in cartilage were between equal levels to and 2.5-fold of those found in plasma, the observed ratios were somewhat lower than those reported for other quinolones, e.g . ofloxacin or sparfloxacin . Since garenoxacin appeared to be well absorbed following oral administration and concentrations in cartilage tended to be higher than those in plasma, it is unlikely that the low chondrotoxicity in comparison with other quinolones is explained by differences in the pharmacokinetics of these compounds.

Drug Ther Bull, 2003 Nov, 41(11), 83 - 6
Antibacterial prophylaxis in surgery: 1--Gastrointestinal and biliary surgery; Quantitation of PGE9509924 et al.; Procter and Gamble Pharmaceuticals, Inc., Health Care Research Center, 8700 Mason-Montgomery Rd, Mason, OH 45040, USA . zoutendam.ph@pg.com

PGE9509924, a novel nonfluorinated quinolone, is a potent antibacterial agent with a broad spectrum of activity . A semi-automated method using 96-well format, solid-phase extraction has been developed for quantitating PGE9509924 in rat plasma . The Waters Oasis HLB extraction plate containing a polymeric packing material was found to give the best overall recoveries . All liquid transfer steps other than aliquoting the plasma are accomplished using a 96-channel pipettor . Reverse-phase HPLC with electrospray/MS/MS detection using selective reaction monitoring is used to quantitate the samples . Stable isotopically labeled PGE9509924 is used as the internal standard . The assay is linear over the range from 0.01 to 10 ug/ml . Excellent precision is obtained within a single run and between multiple runs performed on different days . CVs of <6% were observed . The combination of the semi-automated, 96-well parallel sample processing and the short runtime on the LC/MS/MS results in a high throughput assay with reduced operator interaction.

J Nutr, 2003 Dec, 133(12), 4077 - 82
Zinc oxide protects cultured enterocytes from the damage induced by Escherichia coli; Roselli M et al.; There is some evidence that zinc oxide (ZnO) protects against intestinal diseases . However, despite the suggestions that ZnO may have an antibacterial effect, the mechanisms of this protective effect have not yet been elucidated . We investigated the potential benefits of ZnO in protecting intestinal cells from damage induced by enterotoxigenic Escherichia coli (ETEC, strain K88) and the related mechanisms, using human Caco-2 enterocytes . Cell permeability, measured as transepithelial electrical resistance (TEER), was unaffected by 0.01 and 1 mmol/L ZnO treatments and moderately increased by 5 mmol/L ZnO, compared with untreated cells . Transfer of (14)C-inulin was slightly increased by 5 mmol/L ZnO compared with untreated cells; transfer was unaffected by lower concentrations . The TEER and (14)C-inulin transfer were lower in ETEC-infected cells than in uninfected cells . Treatment of ETEC exposure with 0.2 mmol/L ZnO prevented disruption of membrane integrity . The ETEC was able to adhere to enterocytes and, to some extent, invade the cells . The ZnO treatment reduced bacterial adhesion and blocked bacterial invasion . The ETEC infection upregulated the expression of the inflammatory cytokines interleukin-8, growth-related oncogene-alpha and tumor necrosis factor-alpha, and reduced that of the anti-inflammatory cytokine transforming growth factor-beta, compared with uninfected cells . The addition of 0.2 or 1 mmol/L ZnO counteracted the alteration of cytokine mRNA levels caused by ETEC . The protective effects of ZnO were not due to any antibacterial activity, because the viability of ETEC grown in a medium containing ZnO was unaffected . In conclusion, ZnO may protect intestinal cells from ETEC infection by inhibiting the adhesion and internalization of bacteria, preventing the increase of tight junction permeability and modulating cytokine gene expression.

J Clin Laser Med Surg, 2003 Oct, 21(5), 279 - 82
Cleaning of the root canal using Nd:YAP laser and its effect on the mineral content of the dentin; Moshonov J et al.; OBJECTIVE: The aim of this study was to compare the efficacy of root canal cleanliness with and without Nd:YAP laser and to assess the effect of the laser on the mineral content of the dentin . BACKGROUND DATA: A high degree of cleanliness of the canal when using the Nd:YAG laser has been shown while the laser is in contact with the canal wall . A new Nd:YAP laser has been studied recently, which is considered to be superior to the Nd:YAG with regard to antibactericidal ability due to its 1.34 micro m wavelength, which is in the infra-red range . This wavelength is absorbed better in water than that of Nd:YAG . MATERIALS AND METHODS: Fourteen extracted single rooted premplars were divided into two groups . In group 1, canals were cleaned, instrumented, and shaped with K files . In group 2, initial preparation was done using K files and completed with a Nd:YAP laser . Teeth were then split longitudinally and submitted to scanning electron microscopy . RESULTS: The cleanliness of the laser-treated teeth was significantly greater than teeth treated with K files alone (p < 0.05) . No difference in Ca and P content was detected when the use of K files was compared to the use of laser . CONCLUSION: It appears that the Nd:YAP laser improves the cleanliness of the root canal . However, since the Nd:YAP laser serves as an addition to K files, its clinical value for replacing conventional root canal instrumentation remains to be determined.

Biol Pharm Bull, 2003 Dec, 26(12), 1711 - 4
Synthesis, analgesic, anti-inflammatory and antibacterial activities of some novel 2-methyl-3-substituted quinazolin-4-(3H)-ones; Alagarsamy V et al.; A series of novel 2-methyl-3-substituted quinazolin-4-(3H)-ones have been synthesized by treating (2-methyl-4-oxo-3H-quinazolin-3-yl)dithiocarbamic acid methyl ester with different amines, the starting material dithiocarbamate was synthesized from anthranilic acid . The compounds synthesized were investigated for analgesic, anti-inflammatory and antibacterial activities . All the test compounds exhibited significant activity, the compounds VA2, VA3 and VA4 shown more potent analgesic activity, and the compounds VA3 and VA4 shown more potent anti-inflammatory activity than the reference compound diclofinac sodium.

Am J Ophthalmol, 2003 Dec, 136(6), 1032 - 7
Corneal ciprofloxacin precipitation during bacterial keratitis; Wilhelmus KR et al.; PURPOSE: To examine how age affects the risk of developing a white corneal precipitate during ciprofloxacin therapy for bacterial keratitis and to explore the effect of a white precipitate on rates of clinical improvement and cure . DESIGN: Prospective, multicenter, observational cohort study . METHODS: Occurrence of a white precipitate of the corneal surface was recorded among 624 patients with presumed bacterial keratitis who were treated with topical ciprofloxacin 0.3% solution or ointment . Relative risks of corneal precipitation were estimated from logistic regression for age categories and other clinical characteristics . The time-dependent effects of precipitate on rates of infection resolution and corneal reepithelialization were estimated by proportional hazards regression . RESULTS: Ninety-five (15.2%) patients developed a white corneal precipitate during ciprofloxacin therapy; 72 (75.8%) began within the first 3 days of treatment . Compared with those younger than 40 years old, patients aged 60 to 69 years had 2.8 (95% confidence limits {CL}, 1.9, 3.9) times the risk of ciprofloxacin precipitation; patients 70 years and older had 3.7 (95% CL, 2.6, 5.0) times the risk . Median duration of the visible corneal precipitate was 8.5 days (90% decile, 32 days) . Presence of ciprofloxacin precipitation did not significantly affect the time until therapeutic improvement (P =.09) but slowed the time until reepithelialization by 55% (95% CL 32%, 70%) . CONCLUSIONS: Older patients treated with topical ciprofloxacin for bacterial keratitis have a higher risk of corneal deposition . A white precipitate apparently does not interfere with antibacterial therapeutic response but may delay epithelial healing of ulcerative keratitis.

Bioorg Med Chem Lett, 2003 Dec 15, 13(24), 4395 - 7
Antibacterial and antiproliferative activity of cationic fullerene derivatives; Mashino T et al.; We examined the antibacterial and antiproliferative activities of alkylated C(60)-bis(N,N-dimethylpyrrolidinium iodide) derivatives . The fullerene derivatives inhibited bacteria and cancer cell growth effectively . However, the fullerene derivatives with a long alkyl chain did not show antibacterial activity.

Free Radic Biol Med, 2003 Dec 1, 35(11), 1373 - 81
Nitric oxide promotes strong cytotoxicity of phenolic compounds against Escherichia coli: the influence of antioxidant defenses; Urios A et al.; The induction of mutagenic and cytotoxic effects by simple phenolics, including catechol (CAT), 3,4-dihydroxyphenylacetic acid (DOPAC), hydroquinone (HQ), and 2,5-dihydroxyphenylacetic (homogentisic) acid (HGA), appears to occur through an oxidative mechanism based on the ability of these compounds to undergo autoxidation, leading to quinone formation with the production of reactive oxygen species . This is supported by the detection of such adverse effects in plate assays using Escherichia coli tester strains deficient in the OxyR function, but not in OxyR(+) strains . The OxyR protein is a redox-sensitive regulator of genes encoding antioxidant enzymes including catalase and alkyl hydroperoxide reductase, which would eliminate hydrogen peroxide . Methyl-substituted phenolics such as 4-methylcatechol (MCAT) and methylhydroquinone (MHQ) produced, in addition to oxidative toxicity, marked cytotoxic effects against OxyR(+) cells, thus revealing a mechanism of toxicity not mediated by hydrogen peroxide that could involve quinones and quinone methides arising from MCAT and MHQ oxidation . Quinone compounds could also be responsible for the enhanced cytotoxicity of certain phenolics when combined with a nitric oxide (NO(*)) donor such as diethylamine/NO (DEA/NO) . Phenolics scavenge NO(*) and, in turn, NO(*) oxidizes phenolics to form their quinone derivatives . In OxyR(+) cells, where the oxidative toxicity is inhibited, DEA/NO promoted exceptional increases in the cytotoxicity of CAT and 3,4-dihydroxycinnamic (caffeic) acid (CAF), which both exhibited very low oxidative cytotoxicity, as well as in that of MCAT, HQ, and MHQ . In contrast, DEA/NO failed to promote toxicity by DOPAC and HGA, probably due to their ability to undergo oxidative polymerization, leading to the formation of melanins . Spectroscopic studies demonstrated quinone generation from the oxidation of CAF, HQ, and MHQ by DEA/NO . The o-quinone derived from CAF was rather unstable and decomposed during its isolation . For the generation of toxic quinones, e.g., to be used as therapeutic agents producing antitumor or antibacterial effects, the isolation step could be avoided with the method proposed . It combines quinone precursors, i.e . phenolic compounds, with an oxidant such as NO(*).

Semin Cutan Med Surg, 2003 Sep, 22(3), 196 - 211
Antibiotics in cutaneous medicine: an update; Carter EL; Antibiotics play a vital role in contemporary cutaneous medicine and surgery . They are prescribed more commonly than perhaps any other group of medications with the exception of the corticosteroids . This review discusses the major oral antibacterial agents used in dermatology today, including the beta-lactams, macrolides, tetracyclines, quinolones, sulfonamides, clindamycin, and rifampin.

Trends Genet, 2003 Dec, 19(12), 684 - 7
Arthropod and mollusk defensins--evolution by exon-shuffling; Froy O et al.; Arthropod and mollusk defensins are secreted antibacterial proteins that exhibit similarity in sequence, mode of action and structure and are expressed ubiquitously . Comparison of the gene organization of a newly cloned scorpion defensin gene, with that of other arthropods and the mussel, revealed that all exons and introns, aside from the exon encoding the mature protein, differ widely in number, size and sequence . This variability suggests that the exon encoding the mature defensin has undergone exon-shuffling and integrated downstream of unrelated leader sequences during evolution . Unlike other exon-shuffling events, in which modules are added into existing proteins, arthropod and mollusk defensins represent the first instance of exon-shuffling of autonomous modules.

Zhonghua Yi Xue Za Zhi, 2003 Oct 25, 83(20), 1778 - 81
{Laboratory and clinical study of levofloxacin against Helicobacter pylori}; Zou J et al.; OBJECTIVE: To assess antibacterial activity of levofloxacin to Helicobacter pylori (Hp) strains In Vitro and In Vivo . METHODS: The Minimum inhibitory concentration (MIC) for 52 clinical isolates was detected by agar dilution method and was compared with those of amoxicillin and clarithromycin . To examine the effects of pH variation on the susceptibility of Hp to levofloxacin, Mueller-Hinton agar with 7% defibrinated sheep blood was adjusted to a pH range of 4.0, 5.0, 7.0 by adding hydrochloric acid . 85 Hp-positive Patients with chronic active gastritis or active peptic ulcer disease were consecutively recruited in a prospective, open-label study . The enrolled patients were randomised to receive a seven-day course of omeprazole 20 mg bid plus amoxicillin 1000mg bid and levofloxacin 200mg bid . Their Hp status was assessed by (13)C-urea breath test and/or endoscopy 4 - 6 weeks after the end of treatment . RESULTS: The resistant rates of strains to levofloxacin, amoxicillin and clarithromycin were 1.9%, 11.5% and 25%, respectively . A dual-resistance to amoxicillin and clarithromycin was demonstrated in five Hp strains (9.6%), which were all susceptible to levofloxacin . The prevalence of strains with resistance to levofloxacin was lower than that of strains with resistance to clarithromycin (P < 0.01), and was no statistically different with amoxicillin (P > 0.05) . The activity of levofloxacin was diminished under acidic environment (P < 0.01) . 84 enrolled patients completed the study . 76 patients (PP and ITT analysis, 91.7%; 90.6%) become Hp-negative . Slight side-effects occurred in 5 patients (5.9%) . CONCLUSION: In the present study, we report a high rate of resistance to amoxicillin and clarithromycin in this region . Omeprazole/levofloxacin-based triple therapy, including amoxicillin, is attractive because they combine a high eradication efficacy with an excellent tolerability and safety profile.

Aust Dent J, 2003 Mar, 48(1), 20 - 6
A survey of sodium hypochlorite use by general dental practitioners and endodontists in Australia; Clarkson RM et al.; BACKGROUND: Sodium hypochlorite is used commonly as an endodontic irrigant, but there are no published reports that provide details of its use . This survey sought to determine the percentage of Australian dentists who practiced endodontics, whether they used sodium hypochlorite for irrigation, and the manner of dilution, storage and dispensing sodium hypochlorite used by both dentists and endodontists . METHODS: All Australian endodontists and a stratified random sample of 200 general dentists in Australia were surveyed to address the issues identified above . RESULTS: Almost 98 per cent of dentists surveyed performed endodontic treatment . Among endodontists, nearly 94 per cent used sodium hypochlorite for irrigation compared with just under 75 per cent of general dentists . Sodium hypochlorite use by general dentists was more common in Victoria and South Australia than in other States . An infant sanitizer (Milton or Johnson's Antibacterial Solution) was used by just over 92 per cent of general practitioners and by more than 67 per cent of endodontists . All other respondents used domestic bleach . One hundred and sixty four of the respondents (80 per cent of endodontists and over 90 per cent of general dentists) used a 1 per cent w/v solution . Ten practitioners used a 4 per cent w/v solution, five used a 2 per cent w/v solution and four used a 1.5 per cent w/v solution . Eighty per cent of the practitioners who diluted their sodium hypochlorite before use, used demineralized water for this purpose . The remainder used tap water . Only four practitioners stored sodium hypochlorite in a manner which risked light exposure and loss of available chlorine content . CONCLUSIONS: Sodium hypochlorite is commonly used as an endodontic irrigant and Australian dentists generally stored the material correctly.

Arch Pharm (Weinheim), 2003 Nov, 336(11), 504 - 9
Synthesis and antibacterial activity of 1 beta-methyl-2-(5-substituted imidazolino pyrrolidin-3-ylthio)carbapenem derivatives; Oh CH et al.; The synthesis of a new series of 1 beta-methylcarbapenems containing a substituted imidazolino pyrrolidine moiety is described . Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of the substituent on the imidazoline ring was investigated . Compound 13 g which has a N-sulfonylmethyl substituted imidazoline moiety showed the most potent antibacterial activity.

Arch Pharm (Weinheim), 2003 Nov, 336(11), 495 - 503
Synthesis and antibacterial activities of 4-pyrrolidinylthio carbapenems: containing heteroaromatics as a side chain; Cho HW et al.; The synthesis of a new series of 2-alkyl-4-pyrrolidinylthio-b-methylcarbapenems containing the substituted heteroaromatic moieties is described . Their in vitro antibacterial activities against both gram-positive and gram-negative bacteria were tested . The effect of substituents on the nitrogen atoms at heteroaromatic rings was investigated . Particular compounds (14 b, 14 c) containing 3-methyl- and 3, 5-dimethylpyrazolethio substituted moiety showed the most potent antibacterial activity.

Antimicrob Agents Chemother, 2003 Dec, 47(12), 3859 - 66
Triclosan as a systemic antibacterial agent in a mouse model of acute bacterial challenge; Sharma S et al.; The upsurge of multiple-drug-resistant microbes warrants the development and/or use of effective antibiotics . Triclosan, though used in cosmetic and dermatological preparations for several decades, has not been used as a systemic antibacterial agent due to problems of drug administration . Here we report the striking efficacy of triclosan in a mouse model of acute systemic bacterial infection . Triclosan not only significantly extends the survival time of the infected mice, it also restores blood parameters and checks liver damage induced by the bacterial infection . We believe that the excellent safety track record of triclosan in topical use coupled with our findings qualifies triclosan as a candidate drug or lead compound for exploring its potential in experimental systems for treating systemic bacterial infections.

EMBO J, 2003 Dec 1, 22(23), 6214 - 24
Crystal structure of coproporphyrinogen III oxidase reveals cofactor geometry of Radical SAM enzymes; Layer G et al.; 'Radical SAM' enzymes generate catalytic radicals by combining a 4Fe-4S cluster and S-adenosylmethionine (SAM) in close proximity . We present the first crystal structure of a Radical SAM enzyme, that of HemN, the Escherichia coli oxygen-independent coproporphyrinogen III oxidase, at 2.07 A resolution . HemN catalyzes the essential conversion of coproporphyrinogen III to protoporphyrinogen IX during heme biosynthesis . HemN binds a 4Fe-4S cluster through three cysteine residues conserved in all Radical SAM enzymes . A juxtaposed SAM coordinates the fourth Fe ion through its amide nitrogen and carboxylate oxygen . The SAM sulfonium sulfur is near both the Fe (3.5 A) and a neighboring sulfur of the cluster (3.6 A), allowing single electron transfer from the 4Fe-4S cluster to the SAM sulfonium . SAM is cleaved yielding a highly oxidizing 5'-deoxyadenosyl radical . HemN, strikingly, binds a second SAM immediately adjacent to the first . It may thus successively catalyze two propionate decarboxylations . The structure of HemN reveals the cofactor geometry required for Radical SAM catalysis and sets the stage for the development of inhibitors with antibacterial function due to the uniquely bacterial occurrence of the enzyme.

J Periodontal Res, 2003 Dec, 38(6), 557 - 63
Calprotectin release from human neutrophils is induced by Porphyromonas gingivalis lipopolysaccharide via the CD-14-Toll-like receptor-nuclear factor kappaB pathway; Kido J et al.; OBJECTIVES: Calprotectin is a cytosolic protein with antibacterial action in leukocytes and its level increases in some inflammatory diseases, including periodontal diseases, rheumatoid arthritis and ulcerative colitis . Recently, we found that the lipopolysaccharide of Porphyromonas gingivalis (P-LPS) induced calprotectin release from human neutrophils . P-LPS, a major virulence factor of periodontal pathogens, is known to induce the production and release of inflammatory cytokines through CD14, Toll-like receptor (TLR) and nuclear factor kappaB (NF-kappaB) . In the present study, we investigated whether calprotectin release by P-LPS is induced via the CD14-TLR-NF-kappaB pathway and the cellular mechanism of calprotectin release in human neutrophils . MATERIAL AND METHODS: Human neutrophils were isolated from the peripheral blood of healthy donors and pre-incubated in medium containing antibodies against CD14, TLR2 and TLR4, or several inhibitors of NF-kappaB, microtubules and microfilaments, and then incubated with P-LPS . The calprotectin amount in the culture medium was determined using ELISA, and the nuclear extracts from cells were used for the examination of NF-kappaB binding activity using electrophoretic mobility shift assays . RESULTS: P-LPS increased calprotectin release from neutrophils and its induction was inhibited by anti-CD14 and anti-TLR2 antibodies, but not by two anti-TLR4 antibodies . NF-kappaB inhibitors suppressed P-LPS-induced NF-kappaB binding activity and calprotectin release . The inhibitors of microtubule and microfilament polymerization significantly decreased P-LPS-induced calprotectin release . CONCLUSION: These results suggest that calprotectin release is induced by P-LPS via the CD14-TLR2-NF-kappaB signal pathway in human neutrophils and may be dependent on microtubule and microfilament systems.

J Antibiot (Tokyo), 2003 Sep, 56(9), 755 - 61
Three new chlorine containing antibiotics from a marine-derived fungus Aspergillus ostianus collected in Pohnpei; Namikoshi M et al.; A marine bacterium Ruegeria atlantica (designated as strain TUF-D) was isolated from a glass plate submerged in the coastal water . Three new chlorine containing compounds (1 to approximately 3), together with penicillic acid (4) were obtained from a marine-derived fungus Aspergillus ostianus strain TUF 01F313 isolated from a marine sponge at Pohnpei as antibacterial components against R . atlantica . The structures of three new antibiotics were determined based on their spectral data as 8-chloro-9-hydroxy-8,9-deoxyasperlactone (1), 9-chloro-8-hydroxy-8,9-deoxyasperlactone (2), and 9-chloro-8-hydroxy-8,9-deoxyaspyrone (3) . Compound 1 inhibited the growth of R . atlantica at 5 microg/disc (inhibition zone: 12.7 mm), while 2 and 3 were active at 25 microg/disc (10.1 and 10.5 mm, respectively).

J Biol Chem, 2004 Feb 6, 279(6), 4981 - 7 Epub 2003 Nov 20.
Channel-forming membrane permeabilization by an antibacterial protein, sapecin: determination of membrane-buried and oligomerization surfaces by NMR; Takeuchi K et al.; The action mechanism of sapecin, an antibacterial peptide with membrane permeabilization activity, was investigated . The dose dependence of the membrane permeabilization caused by sapecin was sigmoidal, suggesting that sapecin oligomerization leads to the membrane permeabilization . Solution nuclear magnetic resonance analysis of the sapecin-phospholipid vesicle complex revealed the surface buried in the membrane and oligomerization surface on the sapecin molecule . The membrane-buried surface of sapecin was determined by observing the transferred cross-saturation phenomena from the alkyl chains of the phospholipid vesicle to the amide protons of sapecin . The membrane-buried surface contains basic and highly exposed hydrophobic residues, which are suitable for interacting with the acidic bacterial membrane . The oligomerization surface was also identified by comparisons between the results from hydrogen-deuterium exchange experiments and transferred cross-saturation experiments . On the basis of the results from the NMR experiments we built a putative model of sapecin oligomers, which provides insights into the membrane permeabilization caused by insect defensins.

FEBS Lett, 2003 Nov 27, 555(1), 66 - 71
TolC--the bacterial exit duct for proteins and drugs; Koronakis V; The TolC structure has unveiled a common mechanism for the movement of molecules, large and small, from the bacterial cell cytosol, across two membranes and the intervening periplasm, into the environment . Trimeric TolC is a remarkable cell exit duct that differs radically from other membrane proteins, comprising a 100-A long alpha-barrel that projects across the periplasmic space, anchored by a 40-A long beta-barrel spanning the outer membrane . The periplasmic entrance of TolC is closed until recruitment by substrate-specific translocases in the inner membrane triggers its transition to the open state, achieved by an iris-like 'untwisting' of the tunnel alpha-helices . TolC-dependent machineries present ubiquitous exit routes for virulence proteins and antibacterial drugs, and their conserved structure, specifically the electronegative TolC entrance constriction, may present a target for inhibitors of multidrug-resistant pathogens.

Fitoterapia, 2003 Dec, 74(7-8), 736 - 40
Antibacterial activity of Alstonia scholaris and Leea tetramera; Khan MR et al.; The crude methanolic extracts of the leaves, stem and root barks of Alstonia scholaris and Leea tetramera on partitioning (petrol, dichloromethane, ethyl acetate, butanol) gave fractions exhibiting improved and broader spectrum of antibacterial activity . Especially the butanol fractions of A . scholaris and the root bark of L . tetramera . None of the fractions were active against the fungi tested.

Food Chem Toxicol, 2004 Jan, 42(1), 85 - 91
Sanguinarine and chelerythrine: assessment of safety on pigs in ninety days feeding experiment; Kosina P et al.; Sanguinaria canadesis, Chelidonium majus and Macleya cordata have been used for centuries as alternative medicines . Currently the extracts from these medicinal plants are components of veterinary and human phytopreparations, and of oral-hygiene agents . Sanguinarine and chelerythrine (SA/CHE) are biologically active components of these extracts . They display distinct antibacterial and anti-inflammatory properties, but, on the other hand, they have been reported as having adverse effects - genotoxicity and hepatotoxicity . This paper is aimed at evaluation of the effects of daily administration of the extract from Macleya cordata (2 mg and 100 mg in 1 kg feed, sanguinarine:chelerythrine 3:1) in the diet on the health status of swine . After 90-day administration, alkaloids were retained to a different extent in tissues . The highest SA/CHE retention was detected in the gingiva (0.55 microg/g) and liver (0.15 microg/g), no SA/CHE were detected in muscles . Plasma SA levels attained 0.11 microg/ml . Treated animals did not display any results of hematological, biochemical or histological assay different from controls . A (32)P-postlabeling assay proved that no DNA-adducts with SA/CHE were detected in pig livers . We did not observe any symptom linked to epidemic dropsy syndrome often attributed to sanguinarine . In conclusion, an average daily oral dose of alkaloids up to 5 mg per 1 kg animal body weight proved to be safe.

J Hosp Infect, 2003 Dec, 55(4), 239 - 45
Hand hygiene and skin health; Kownatzki E; The high rate of hand problems associated with the hand hygiene of medical professions is due to a combination of damaging factors: (1) the removal of barrier lipids by detergent cleaning and alcohol antisepsis followed by a loss of moisturizers and stratum corneum water and (2) the overhydration of the stratum corneum by sweat trapped within gloves . Together the facilitate the invasion of irritants and allergens which elicit inflammatory responses in the dermis . Among the lipids and water-soluble substances removed are natural antibacterials . Their loss leads to increased growth of transient and pathogenic micro-organisms which jeapordizes the very intention of skin hygiene . The kinetics of damage and its repair, and epidemiological evidence suggest that modern synthetic detergents as used in foaming liquid cleansers are the major offender . Conversely, the replacement of detergents with non-detergent emulsion cleansers has been shown to be effective in reducing the prevalence of hand problems among hospital staff . Presently recommended hand antisepsis reduces the risks to patients, but puts the burden on the health care provider . Rather than fighting micro-organisms at the expense of the skin's health, the skin and its own defences should be considered a collaborator in combating infectious diseases.

Paediatr Perinat Epidemiol, 2003 Oct, 17(4), 340 - 6
Signs of infection in Pap smears and risk of adverse pregnancy outcome; Buchmayer S et al.; Previous studies on whether signs of infection in Pap smears imply a risk factor for preterm delivery are conflicting . In a large population-based study, we combined information from the Swedish Medical Birth Register and the Swedish Pap Smear Screening Register to investigate whether signs of infection in Pap smears increase the risks of adverse pregnancy outcomes . Logistic regression analyses were used to estimate odds ratios (OR) for antepartum death, preterm or small-for-gestational-age delivery . The presence of Coccobacilli or Trichomonas vaginalis in Pap smears increased the risk of small-for-gestational-age delivery (OR 1.3 and 1.4, respectively) . Signs of infection in Pap smears were generally not associated with an increased risk of antepartum death or preterm birth . However, the presence of Coccobacilli in Pap smears within 4 weeks before delivery was associated with a more than fourfold increase in risk of very preterm delivery (< or =31 weeks, OR 4.7) . This indicates that if Coccobacilli are detected in Pap smears during the second trimester, antibacterial treatment may lower the risk of very preterm delivery.

Antibiot Khimioter, 2003, 48(7), 29 - 32
{Cefepime/amikacin in the empirical antibacterial therapy for patients with hemoblastosis of different forms}; Chudanova TV et al.; The results of the use of cefepime (Maxipime) combination with amikacin vs ceftriaxon combination with amikacin in the treatment of 80 patients with different forms of hemoblastosis are presented . Severe infectious complications in the patients were associated with prolonged and deep neutropenia during inductive or antirelapsing chemotherapy . All the patients in the trial were from the group of high risk of infectious complications with the blood neutrophil count under 100 cells/microliter . The duration of neutropenia averaged 12 days (7 to 15) . The average period of the treatment with cefepime and amikacin equaled to 13 days (8 to 16) . The treatment with cefepime + amikacin was successful in 38 out of 40 patients (95%) . The average period of the treatment with ceftriaxon and amikacin equaled to 14 days (7 to 18) . The efficacy of the treatment with ceftriaxon + amikacin was 60% (24 patients out of 40).

Adv Drug Deliv Rev, 2003 Nov 28, 55(12), 1679 - 98
Collagen as a carrier for on-site delivery of antibacterial drugs; Ruszczak Z et al.; Due to its biocompatibility and well-established safety profile, collagen represents a favourable matrix for on-site drug delivery . In this review, we summarize some of the recent developments and applications of collagen as a biomaterial in drug delivery systems for antibiotics, especially gentamicin . The main clinical and experimental applications covered include: treatment and prophylaxis of bone and soft tissue infections, wound healing, as well as ophthalmic and periodontal treatment . Advantages of local drug application and the rationale of use local drug delivery systems for adjuvant (ancillary) therapy are discussed . Recent efforts in the use of collagen and collagen-synthetic polymer composites for controlled drug delivery as well as collagen-based diffusion membranes for prolonged drug release have also been included in this review.

Bioorg Med Chem Lett, 2003 Dec 1, 13(23), 4235 - 9
The effect of remote chirality on the antibacterial activity of indolinyl, tetrahydroquinolyl and dihydrobenzoxazinyl oxazolidinones; Ciske FL et al.; The oxazolidinones are promising agents for the treatment of infections caused by gram-positive bacteria, including multidrug-resistant strains . In ongoing studies we have discovered that a strategically placed chiral center of appropriate absolute configuration improves the antibacterial activity of indolinyl oxazolidinone analogues (gram-positive MIC's<0.5 microg/mL for the most potent congeners) . The design, synthesis, antibacterial activity and pharmacokinetic profile of a selected series of alpha-methylated indoline derivatives and a related set of tetrahydroquinolyl and dihydrobenzoxazinyl analogues are discussed.

Bioorg Med Chem Lett, 2003 Dec 1, 13(23), 4229 - 33
Structure-activity relationship in the oxazolidinone-quinolone hybrid series: influence of the central spacer on the antibacterial activity and the mode of action; Hubschwerlen C et al.; Oxazolidinone-quinolone hybrids, which combine the pharmacophores of a quinolone and an oxazolidinone, were synthesised and shown to be active against a variety of susceptible and resistant Gram-positive and Gram-negative bacteria . The nature of the spacer greatly influences the antibacterial activity by directing the mode of action, that is quinolone- and/or oxazolidinone-like activity . The best compounds in this series have a balanced dual mode of action and overcome all types of resistance, including resistance to quinolones and linezolid, in clinically relevant Gram-positive pathogens.

Bioorg Med Chem Lett, 2003 Dec 1, 13(23), 4223 - 8
Alpha-substituted hydroxamic acids as novel bacterial deformylase inhibitor-based antibacterial agents; Jain R et al.; We report the synthesis and biological activity of analogues of VRC3375 (N-hydroxy-3-R-butyl-3-{(2-S-(tert-butoxycarbonyl)-pyrrolidin-1-ylcarbonyl}propionamide), an orally active peptide deformylase inhibitor . This study explores the structure-activity relationship of various chelator groups, alpha substituents, P(2)' and P(3)' substituents in order to achieve optimal antibacterial activity with minimal toxicity liability.

Bioorg Med Chem Lett, 2003 Dec 1, 13(23), 4197 - 200
Synthesis and biological evaluation of benzazepine oxazolidinone antibacterials; Johnson PD et al.; Novel benzazepine oxazolidinone antibacterials were synthesized and evaluated against clinically relevant susceptible and resistant organisms . The effect of ring nitrogen position and N-substitution on antibacterial activity is examined.

Bioorg Med Chem Lett, 2003 Dec 1, 13(23), 4193 - 6
The synthesis and antibacterial activity of 1,3,4-thiadiazole phenyl oxazolidinone analogues; Thomasco LM et al.; Replacement of the morpholine C-ring of linezolid 1 with a 1,3,4-thiadiazolyl ring leads to oxazolidinone analogues 5 having potent antibacterial activity against both gram-positive and gram-negative organisms . Conversion of the C5 acetamide group to a thioacetamide further increases the potency of these compounds.

Bioorg Med Chem Lett, 2003 Dec 1, 13(23), 4187 - 91
Synthesis and biological activity of N-Acylated ornithine analogues of daptomycin; Hill J et al.; N-Acylated ornithine analogues of daptomycin were synthesized and tested for their antibacterial efficacy.

Bioorg Med Chem Lett, 2003 Dec 1, 13(23), 4179 - 86
New classes of antibacterial oxazolidinones with C-5, methylene O-linked heterocyclic side chains; Gravestock MB et al.; Exploration of the structure-activity relationships of the traditional C-5 acetamidomethyl side chain of the oxazolidonone antibacterials has yielded new, potent series of compounds of which the first examples, the O-linked iosoxazoles are described in detail, leading to the selection of the pre-clinical candidate AZD2563.

Bioorg Med Chem Lett, 2003 Dec 1, 13(23), 4173 - 7
Synthesis and antibacterial activity of pyrroloaryl-substituted oxazolidinones; Paget SD et al.; A novel series of oxazolidinones containing a pyrroloaryl substituent was synthesized and screened against a representative panel of susceptible and resistant Gram-positive bacteria . Several members of this series were found to have antibacterial activity comparable to or better than linezolid.

Bioorg Med Chem Lett, 2003 Dec 1, 13(23), 4169 - 72
Influence of ethylene-oxy spacer group on the activity of linezolid: synthesis of potent antibacterials possessing a thiocarbonyl group; Selvakumar N et al.; The influence of an ethylene-oxy spacer element between the heterocycle and the aromatic ring in linezolid is reported . The introduction of such spacer group generated compounds with inferior antibacterial activity . However, the conversion of the acetamide group present in the linezolid analogues to either thiocarbamate or thioacetamide functionality restored the activity . The synthesis of linezolid analogues possessing the ethylene-oxy spacer group along with SAR studies with different heterocycles and preparation of some thiocarbonyl compounds possessing potent antibacterial property are presented.

Bioorg Med Chem Lett, 2003 Dec 1, 13(23), 4165 - 8
Semi-synthetic glycopeptide antibacterials; Judice JK et al.; Studies leading to the discovery of TD-6424 and their relevance to other hydrophobically-substituted glycopeptides are reviewed along with a brief comparison of properties for related agents currently undergoing clinical evaluation.

Mycoses, 2003, 46(9-10), 418 - 21
Fatal pulmonary scedosporiosis; Horre R et al.; We report on a case of scedosporiosis in a 72-year-old German woman . Her disease started with a purulent ulceration of unknown course at her left foot . Soon after onset of oral antibacterial therapy she needed in-hospital treatment because of an acute pneumonia . The infection progressed despite the application of different antibiotics . Microscopic examination of tracheal fluid revealed fungal hyphae and therefore treatment with itraconazole was initiated . However, the patient developed renal failure, required mechanical ventilation and finally died in treatment-resistant septic shock . Post-mortem Scedosporium apiospermum was cultured from lung tissue taken during autopsy . This is the fourth case of human infection caused by Scedosporium species diagnosed in our laboratory during the last 4 years.

Prescrire Int, 2003 Oct, 12(67), 184 - 9
Acute otitis media in children: amoxicillin remains the standard antibiotic, but justified in certain situations only.
{Effects of Fall-39 mRNA expression and antibacterial activity of human pulmonary gland epithelial cells induced by BCG}
Zhu L, Feng Y, Huang N, Wang B, Chen J.

Department of Pharmacology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu 610041, ChinaOBJECTIVE: To disclose whether BCG can enhance Fall-39 gene expression in human pulmonary gland epithelial cells, and to isolate and identify the bioactive proteins that stimulate Fall-39 gene expression in human pulmonary gland epithelial cells . METHODS: Fall-39 mRNA expression in SPC-A-1 cells was detected by using RT-PCR . The cell wall proteins were isolated by sucrose density-gradient centrifugation and fractionated by Sephadex G-75 column chromatography . The antibacterial activity of the cell culture supernatant was determined by agarose radial diffusion assay . RESULTS: The enhanced expression of Fall-39 mRNA was dose- and time-dependent . BCG cell wall proteins fraction 4 had an activity that remarkably enhanced Fall-39 mRNA expression in SPC-A-1 cells and augmented antibacterial activity of the cell culture supernatant . CONCLUSION: These results indicated that BCG could stimulate Fall-39 mRNA expression in human pulmonary gland epithelial cells, thus providing an evidence base for shaping well a new strategy to enhance mucosa antibiotic peptide expression for the prevention and treatment of mucosal infections.

Mikrobiol Z, 2003 Jul-Aug, 65(4), 68 - 76
{Antibacterial activity of pure cultures of cyanobacteria and algae}; Gol'din EB; Pure cultures of Microcystis aeruginosa, Platymonas viridis and Nephrochloris salina have been grown on the media with different nitrogen and phosphorus content . Their supernatants and pellets, as well as lipid complex, terpene fraction and some its components from M . aeruginosa had selective antibacterial characteristics . The increase of nitrogen content in the medium correlated with the intensification (M . aeruginosa, N . salina) or conservation (P . viridis) of bactericidal activity . The pellet fraction was more active than supernatant (P . viridis) one . The specific cyanobacterial and microalgal inhibitory effect is supposed with respect to the organisms of different evolutionary level.

Clin Exp Allergy, 2003 Nov, 33(11), 1518 - 25
Early-life exposure to antibacterials and the subsequent development of hayfever in childhood in the UK: case-control studies using the General Practice Research Database and the Doctors' Independent Network; Bremner SA et al.; BACKGROUND : Theoretically, antibacterial agents in early life might influence allergic sensitization in two ways: (i) as an indicator of infectious illness, they might be expected to protect against allergy; (ii) alternatively they might increase the risk through effects on the commensal bowel flora . Epidemiological evidence linking the prescription of antibacterial agents in early life to the subsequent development of hayfever is conflicting . OBJECTIVE : To establish definitively whether an association exists between early-life antibacterial exposure and childhood hayfever diagnosis . METHODS : Nested case-control studies were based on birth cohorts of children identified within two large UK general practice databases of electronic patient records . One hundred and sixteen thousand and four hundred and ninety-three children from 605 general practices were identified as being continuously registered from birth to at least age 5 years . Seven thousand and ninety-eight cases were diagnosed with hayfever after the age of 2 years . One control per case was matched for practice, birth month, sex and still being registered on case diagnosis date . Odds ratios were derived from conditional logistic regressions within each database followed by pooling using a fixed-effect model . RESULTS : The pooled odds ratio for hayfever was 1.11, 95% CI (1.03-1.20) if exposed to antibacterials in the first year of life, 1.35 (1.25-1.46) in year 2 and 1.47 (1.37-1.59) in year 3 . Adjusting for consultation frequency reduced these odds ratios to 0.92, 1.05 and 1.10, respectively . There was no evidence that broader spectrum antibacterials, exposure in any specific month of year 1 or in the grass pollen season influenced the risk of hayfever . CONCLUSION : These data exclude any important effect of antibacterial exposure in infancy on subsequent hayfever risk . Associations reported in earlier studies have likely been exaggerated through publication bias and by lack of control for the tendency of some families to consult frequently for a range of conditions.

J Gastroenterol, 2003, 38(10), 921 - 9
Gastric low-grade B-cell MALT lymphoma: treatment, response, and genetic alteration; Nakamura T et al.; Approximately 10% of gastric low-grade B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) type are unresponsive to Helicobacter pylori ( H . pylori) eradication treatment, and many of them contain an API2-MALT1 chimeric transcript mediated by t(11;18)(q21;q21) translocation . We here review the current status on the interrelationship among clinical features, H . pylori infection status, responsiveness to antibacterial treatment, and API2-MALT1 chimeric transcript of gastric MALT lymphoma in a unicenter study experience and discuss the clinicopathologic significance of API2-MALT1 chimeric transcript in gastric MALT lymphoma . We enrolled 59 patients with gastric MALT lymphoma in a unicenter study . H . pylori infection status and clinical stages were investigated . Antibacterial treatment and subsequent follow-up endoscopy were performed for the assessment of responsiveness of MALT lymphoma in every patient . All cases were examined for API2-MALT1 chimeric transcript by means of RT-PCR and sequencing analyses using RNA extracted from tissues . H . pylori infection status was assessed as positive in 50 patients and negative in 9 . Antibacterial treatment achieved complete or partial remission in 41 patients and no change in 12 . API2-MALT1 chimeric transcript was detected in 9 patients, all of whom showed no change in response to treatment . Notably, responsiveness to H . pylori eradication treatment most clearly delineated the enrolled cases into two groups, indicating that six factors ( H . pylori infection, API2-MALT1 chimeric transcript, cobblestone mucosa and submucosal tumor in gross appearance, nodal involvement, and clinical stage) were statistically significant . On the other hand, comparison of two groups from the standpoint of H . pylori or API2-MALT1 chimeric transcript status revealed a lesser number of the statistically significant factors (two and three, respectively) . Gastric MALT lymphoma characterized by unresponsiveness to antibacterial treatment contains all API2-MALT1 chimeric transcript-positive cases and may constitute a distinct group often seen with nodal involvement and an advanced clinical stage . This group is thought to be unrelated to H . pylori infection in its pathogenesis, and might share a unifying feature of genetic alteration such as involving the MALT1 locus on chromosome 18 . Investigation in the future will clarify this issue and establish the clinical implication of such genetic alteration as the predictive factor for gastric MALT lymphoma.

Biol Reprod, 2004 Mar, 70(3), 768 - 74 Epub 2003 Nov 12.
Involvement of semenogelin-derived peptides in the antibacterial activity of human seminal plasma; Bourgeon F et al.; Mechanisms for protecting spermatozoa, and the testes that produce them, from infection are essential, given the importance of these cells and organs for the fertility of the individual and perpetuation of the species . This is borne out by the publication of numerous papers on this subject over the last 50 years . We extended our work and that of others on the anti-infectious defense system of the male genital tract, using a new strategy for the direct identification of antibacterial molecules in human seminal plasma . We subjected a liquefied seminal plasma cationic fraction to reversed-phase HPLC, monitored microbicidal activity by gel overlay and radial diffusion assays, and identified the proteins and/or peptides present in each active fraction by mass spectrometry . In addition to proteins with known potent microbicidal activity--phospholipase A2, lactoferrin, and lysozyme--we also found that peptides produced by cleavage of semenogelin I, the predominant human semen coagulum protein, had high levels of antibacterial activity.

Klin Khir, 2003 Aug, (8), 38 - 40
{Extrapleural thoracoplasty and its place in the tuberculosis epidemic environment}; Duzhyi; The end of 20th century have been noted by tendency of the tuberculosis expansion up to epidemic occurrence in some countries . Primary and secondary resistance of tuberculosis mycobacterium toward antibacterial preparations and the wide-spread affection, which constitute contraindications to pulmonary resection performance, are revealing more and more . Not rarely the patient's general condition didn't permit to perform radical intervention . The author proposes extrapleural thoracoplasty performance as an alter-native and suggests indications to it.

Nahrung, 2003 Oct, 47(5), 286 - 90
Chemical composition and antibacterial activities of lupin seeds extracts; Lampart-Szczapa E et al.; Determination of influence of lupin natural phenolic compounds on antibacterial properties of its seeds was carried out . Raw material were seeds of Lupinus albus, L . luteus, and L . angustifolius . The methods included the determination of the content of proteins, total phenolic compounds, free phenolic acids, and tannins as well as antibacterial properties with ethanol extracts . The content of total phenolic compounds was smaller in testas than in cotyledons and the highest levels are observed in bitter cultivars of Lupinus albus cv . Bac and L . angustifolius cv . Mirela . Lupin tannins mainly occurred in cotyledons of the white lupin, predominantly in the bitter cultivar Bac . Free phenolic acids were mainly found in testas . Only extracts from the testas displayed antibacterial properties, which excludes the possibility of alkaloid influence on the results . The results suggest that inhibition of test bacteria growth depended mainly upon the content of the total phenolic compounds.

Trends Microbiol, 2003 Nov, 11(11), 519 - 26
Glucose-regulated stress proteins and antibacterial immunity; Rapp UK et al.; The role of stress proteins in immunity and their feasibility as vaccine vehicles against infectious disease have been the focus of intensive examination . Endoplasmic reticulum (ER)-resident stress proteins in particular are interesting model proteins as they perform crucial functions in an organelle that responds promptly to cell stress . We describe transcriptional regulation of ER-resident stress proteins, their involvement in the cellular response to infection and discuss their potential as vaccine candidates against infectious diseases.

Clin Pharmacokinet, 2003, 42(14), 1287 - 304
Transdermal penetration of topical drugs used in the treatment of acne; Krautheim A et al.; Acne vulgaris is a very common skin disease . Most patients present with mild to moderate acne comedonica or papulopustulosa grade I-II . The first-line treatment for these cases is generally via the topical route, whereas systemic medication is indicated when higher severity grades with small nodes or scarring occur . There are several topical agents available that affect at least one of the main pathogenetic factors responsible for the development of acne: hyperseborrhoea, hyperkeratosis, microbial colonisation and inflammatory and immunological reactions . Topical retinoids have a comedolytic and anticomedogenic activity, and some of them have anti-inflammatory potency . Azelaic acid and benzoyl peroxide have a moderate to strong antibacterial effect without inducing bacterial resistance, which is becoming a significant problem with the increasing use of topical antibacterials . Topical antiandrogens may soon be available for the treatment of the pathogenetic factor hyperseborrhoea . The transdermal penetration and the resulting systemic bioavailability of the various topical agents has not been widely considered . Apart from the retinoids, which can be associated with the risk of embryotoxicity/teratogenicity, and clindamycin, which might cause pseudomembranous colitis, information on the systemic pharmacokinetics of other topical agents is not readily available . There is still no consensus on the safe use of topical retinoids in pregnancy, and the occurrence of pseudomembranous colitis after the topical use of clindamycin does not appear to be of clinical relevance . In general, topical anti-acne agents are well tolerated and, as would be expected from their limited transdermal uptake, other significant safety concerns have not so far arisen.

J Endod, 2003 Oct, 29(10), 654 - 7
Evaluation of cytotoxicity of MTAD using the MTT-tetrazolium method; Zhang W et al.; Previous studies have shown that MTAD (a mixture of a tetracycline isomer, an acid, and a detergent) is an effective antibacterial irrigant as a final rinse to remove the smear layer from the instrumented surface of root canals . In this investigation we examined the cytotoxicity of MTAD compared with that of commonly used irrigants and medications . L929 fibroblasts were grown on cell culture plates and were placed in contact with various concentrations of test irrigants and medications . The cytotoxicity of these materials was evaluated 24 h after incubation using MTT assay . Means and standard deviations of absorbance were calculated for each group and statistically analyzed to determine presence or absence of significant difference between the means . The 50% inhibitory dose values were calculated, ranked, and statistically analyzed using the sign interval for median . Based on our results it seems that MTAD is less cytotoxic than eugenol, 3% H2O2, Ca(OH)2 paste, 5.25% NaOCl, Peridex, and EDTA and more cytotoxic than 2.63%, 1.31%, and 0.66% NaOCl.

Boll Chim Farm, 2003 Jul-Aug, 142(6), 242 - 3
Inhibition of herpes simplex virus type 1 by aqueous extracts from leaves of Helichrysum litoreum Guss; Guarino C et al.; Helichrysum litoreum Guss, a Campania medicinal plant reported to have antibacterial properties, was evaluated for antiviral activity against herpes simplex virus type 1 (HSV-1) in vitro . The crude aqueous extract from leaves of Helichrysum litoreum at a concentration of 1.35 mg/ml (ww/v) showed significant antiviral activity on HSV-1 in human lung fibroblast as demonstrated by the absence of a cytopathic effect.

Clin Tech Small Anim Pract, 2003 Aug, 18(3), 186 - 92
Corneal fungal disease in small animals; Andrew SE; Corneal fungal diseases, including fungal keratitis and stromal abscess, are uncommon in small animals . Ocular infection secondary to systemic mycosis is reported far more frequently . Suspicion of a fungal corneal ulcer should be raised based on a history of underlying trauma, especially with plant material, geographic location, chronic use of topical antibiotics or corticosteroids, or an extremely prolonged course of disease despite appropriate treatment . Clinical signs observed with fungal keratitis may include blepharospasm, epiphora, miosis, corneal opacity, and vascularization . Unfortunately, none of these signs is specific to fungal infection . If fungal keratitis is suspected or confirmed, then aggressive medical therapy should be instituted . Medications used include topical antifungals, parasympatholytics, anticollagenases, and antibacterials as well as systemic anti-inflammatory drugs . Because there are very few fungicidal medications, the course of medical treatment for fungal corneal disease requires a prolonged duration with frequent re-examination and assessment . Surgical treatment is sometimes required to save the eye and vision . Surgeries to be considered include debridement, conjunctival graft placement, and corneal transplantation.

J Wound Care, 2003 Oct, 12(9), 351 - 4
Clinical performance of a new silver dressing, Contreet Foam, for chronic exuding venous leg ulcers; Karlsmark T et al.; OBJECTIVE: This study aimed to evaluate the safety and performance of a new sustained silver-releasing dressing, Contreet Foam (Coloplast A/S), in the treatment of moderately to highly exuding chronic venous leg ulcers in which healing is delayed due to the presence of bacteria . METHOD: The clinical performance of Contreet Foam was studied for four weeks in 25 patients with moderately to highly exuding delayed-healing venous leg ulcers . Healing was assessed on a weekly basis with reference to the wound-bed tissue composition, degree of odour and pain, dressing performance and the dressing's effect on the peri-ulcer area . Blood samples were analysed for silver content . RESULTS: Twenty-three out of 25 patients completed the study . One ulcer healed and no wound infections occurred during the study period . A mean 56% reduction in ulcer area (from 15.6 to 6.9 cm2) was recorded during the four weeks, and there was a mean 25% reduction in granulation tissue from dull to healthy after one week . Wound odour reduced significantly after one week . Mean dressing wear time was 3.1 days, and there were only minimal incidences of leakage . Serum silver levels did not exceed reference values . CONCLUSION: Contreet Foam was found to be safe and performed well when used in the treatment of delayed-healing chronic venous leg ulcers, combining effective antibacterial properties with excellent exudate management . DECLARATION OF INTEREST: This study was supported by Coloplast A/S, Humlebaek, Denmark.

J Wound Care, 2003 Oct, 12(9), 331 - 4
An investigation into the wound-healing properties of essential oil of Ocimum gratissimum linn; Orafidiya LO et al.; OBJECTIVE: To investigate the effects of Ocimum oil and two antibacterial preparations, Cicatrin (GlaxoWellcome) and Cetavlex (AstraZeneca), on the healing of full-thickness excisional and incisional wounds, created under anaesthesia, on the back of test and control groups of adult albino rabbits . METHOD: Treatment was by topical application of the test substances onto the wound surface for 15 days . Observation continued for a further six days . Quantitative parameters of wound healing were determined daily . Swabs were taken from wound sites that appeared not to be healing for identification of wound contaminants and sensitivity tests . RESULTS: There was a marked enhancement in the inflammatory and proliferative phases of wound healing in the rabbits treated with Ocimum oil, suggesting that the oil facilitated the healing process to a greater extent than the control and reference products . Wounds treated with Cetavlex showed no sign of healing for eight days but responded to Ocimum oil after a three-day wash-out period . CONCLUSION: The essential oil Ocimum gratissimum can promote wound healing . However, large studies will need to be carried out using domestic pigs, followed by clinical trials on human wounds . DECLARATION OF INTEREST: None.

Biol Pharm Bull, 2003 Nov, 26(11), 1585 - 90
Restorative effect of repetitive administration of Shaoyao-Gancao-tang on bioavailability of paeoniflorin reduced by antibacterial synthetic drugs treatment in rats; He JX et al.; Paeoniflorin (PF) is an active glucoside in Shaoyao (peony root), and is transformed into an antispasmodic metabolite, paeonimetabolin-I (PM-I), by intestinal bacteria in the gut after oral administration of Shaoyao or Shaoyao-Gancao-tang (SGT, Shakuyaku-Kanzo-To in Japanese) . SGT is a pain-relieving traditional Chinese formulation (Kampo-medicine in Japanese) and is often used together with antibacterial synthetic drugs, such as amoxicillin and metronidazole (AMPC-MET), in peptic ulcer therapy . Since the bioavailability of PF in SGT has been reported to be significantly reduced by co-administered antibacterial drugs, we investigated how to minimize this reducing effect of antibacterial treatment in the present study . We found that repetitive administration of SGT starting 24 h after AMPC-MET treatment rapidly restored the plasma PM-I concentration from SGT reduced by AMPC-MET, due to its restorative effect on the decreased PF-metabolizing activity of intestinal bacteria in rat feces . The present findings suggest that it may be clinically useful to administer SGT repetitively, starting 1 or 2 d after treatment with a mixture of AMPC-MET during their combination therapy, to accelerate the recovery of the reduced bioavailability of PF in SGT . Similar administration regimens may also be useful in other combination therapies involving traditional Chinese formulations and antibacterial synthetic drugs to ensure the efficacy of the bioactive glycosides in the formulations.

Masui, 2003 Oct, 52(10), 1110 - 4
{A case of acute pneumococcal meningitis treated with spinal drainage and vancomycin administration}; Fujita A et al.; A 25-year-old woman complaining of general fatigue, headache, high fever, and nuchal rigidity, was admitted . She was diagnosed as pneumococcal meningoencephalitis after the cell culture of cerebrospinal fluid (CSF) . Despite the administration of vancomycin (VCM), she fell into a coma without amelioration of the symptom . VCM was replaced by pipellaciline because antibacterial sensitivity showed the pneumococci were sensitive to the penicillins . She remained unconscious showing progressive hydrocephalus after the open drainage operation . The lumbar drainage at the L 4-5 level and the intrathecal administration of VCM were performed to improve the mal-circulation of CSF . After the procedure, the cell count of CSF showed a significant decrease and her consciousness level was recovered gradually . The patients with pneumococcal meningitis may occasionally require the lumbar drainage with the intrathecal administration of appropriate antibiotics, in case they fail to show response to the conventional therapy.

Klin Med (Mosk), 2003, 81(9), 65 - 8
{Rational antibiotic therapy of pneumonia}; Tereshchenko IV et al.; The aim of the study was to analyse antibacterial treatment in patients with extrahospital pneumonians in a standard pulmonological department . The analysis covered 80 patients with EHP treated in 2000 . In the 100% cases the choice of the antibiotics was random and did not depend on pneumonia severity, age, sex, occupation of the patient, concomitant pathology, the disease duration, previous treatment . Gentamycin was prescribed most frequently . The course doses of the drugs were often violated . The mean hospital stay was 22.5 days, complete resolution was observed only in 8.75% patients.

Bioorg Med Chem Lett, 2003 Nov 17, 13(22), 3915 - 8
Synthesis of linked carbohydrates and evaluation of their binding for 16S RNA by mass spectrometry; Wu B et al.; A library of linked molecules were synthesized from the common sugar moieties existing in the natural amino glycosides . These linked molecules were screened against bacterial 16S RNA for their binding affinity using a mass spectrometry-based technology . Some of these compounds exhibited low micromolar affinity and could serve as leads for further development as antibacterial agents.

Rapid Commun Mass Spectrom, 2003, 17(21), 2373 - 9
Fragmentation pathways of sulphonamides under electrospray tandem mass spectrometric conditions; Klagkou K et al.; Sulphonamides are antibacterial compounds used extensively in farming and veterinary practice . Residues are commonly found in meat and milk . The growing concern about antibiotic resistance of bacteria led to a lowering of the legal concentration limits of sulphonamides in food . A range of analytical methods, employing tandem mass spectrometry (MS/MS) and selected reaction monitoring (SRM), have been developed to allow screening at the limit of detection (LOD) levels . Interest was drawn to the fragment ions produced by the sulphonamides, some involving complex rearrangements that have not previously been looked at . Here we report an investigation into the fragmentation pattern of sulphonamides under electrospray (ES) MS/MS conditions using ion trap and Fourier transform ion cyclotron resonance (FTICR) mass spectrometers . Structures are proposed for the main fragment ions observed for a range of sulphonamides, the effects of the functional groups in the dissociation pathway of the compounds are investigated, and the mechanisms leading to the main fragment ions are explored .

J Med Chem, 2003 Nov 6, 46(23), 5021 - 30
Poly(ethylene glycol) transport forms of vancomycin: a long-lived continuous release delivery system; Greenwald RB et al.; The facile reaction of vancomycin with various PEG linkers, at the V(3) position, has been selectively accomplished by using an excess of base in DMF . Using rPEG as a blocking group for V(3) provides crystalline derivatives that can be further PEGylated to give pure V(3)-X(1) latentiated species (transport forms) . V(3) tetrameric species were also prepared in order to increase the loading of drug on PEG . All PEG-vancomycin transport forms show significant antibacterial activity that is on the same order of native vancomycin . Significant increases in the AUC were observed for all PEG-vancomycin conjugates thus making them potential single dose therapies.

J Med Chem, 2003 Nov 6, 46(23), 4830 - 3
Dissociation of antibacterial and hemolytic activities of an amphipathic peptide antibiotic; Qin C et al.; Using an alanine-scanning method, we have found that the antibacterial and hemolytic activities of the amphipathic cyclic decapeptide antibiotic tyrocidine A depend on different structural components . Single substitution of glutamine-6 of the natural product with a cationic amino acid results in a therapeutic index enhancement of up to 140-fold . Successful dissociation of the two intimately associated properties should enable discovery of novel analogues with both high bacterial selectivity and antibacterial potency to counter microbial resistance.

J Periodontol, 2003 Sep, 74(9), 1361 - 7
Effect of non-surgical periodontal therapy on glycemic control in patients with type 2 diabetes mellitus; Rodrigues DC et al.; BACKGROUND: The literature suggests that an alteration in glucose metabolism occurs as a result of antibacterial periodontal therapy . The objective of this study was to monitor the effect of non-surgical periodontal therapy on glycemic control in patients with type 2 diabetes mellitus (DM) . METHODS: Thirty type 2 DM subjects with periodontitis were randomly divided into two groups . Group 1 (G1), 15 subjects, received one-stage full-mouth scaling and root planing (FMSRP) plus amoxicillin/clavulanic acid 875 mg; group 2 (G2), 15 patients, received only FMSRP . At baseline and after 3 months, the glycated hemoglobin (HbA1c) values, fasting glucose, and clinical parameters (with computerized probing and individualized acrylic stents) were recorded . Following therapy, the subjects were enrolled in a 2-week interval maintenance program for 3 months . RESULTS: After treatment, both groups showed clinical improvements . A probing depth (PD) reduction of 0.8 +/- 0.6 mm (P < 0.05) occurred in G1 and 0.9 +/- 0.4 mm in G2 (P < 0.05), but there were no significant changes in attachment level . Treatment reduced the HbA1c values after the 3-month observation period in both groups; however, the reduction in HbA1c values for the G2 group was statistically significant, but not for the G1 group . The changes in fasting glucose levels were not significant for either group . CONCLUSIONS: Periodontal therapy improved glycemic control in patients with type 2 DM in both groups; however, the reduction in HbA1c values reached statistical significance only in the group receiving scaling and root planing alone {correction}.

Mar Biotechnol (NY), 2004 Jan-Feb, 6(1), 37 - 52 Epub 2003 Nov 03.
Marine pharmacology in 2000: marine compounds with antibacterial, anticoagulant, antifungal, anti-inflammatory, antimalarial, antiplatelet, antituberculosis, and antiviral activities; affecting the cardiovascular, immune, and nervous systems and other miscellaneous mechanisms of action; Mayer AM et al.; During 2000 research on the pharmacology of marine chemicals involved investigators from Australia, Brazil, Canada, Egypt, France, Germany, India, Indonesia, Israel, Italy, Japan, the Netherlands, New Zealand, Phillipines, Singapore, Slovenia, South Korea, Spain, Sweden, Switzerland, United Kingdom, and the United States . This current review, a sequel to the authors' 1998 and 1999 reviews, classifies 68 peer-reviewed articles on the basis of the reported preclinical pharmacologic properties of marine chemicals derived from a diverse group of marine animals, algae, fungi, and bacteria . Antibacterial, anticoagulant, antifungal, antimalarial, antiplatelet, antituberculosis, or antiviral activity was reported for 35 marine chemicals . An additional 20 marine compounds were shown to have significant effects on the cardiovascular and nervous system, and to possess anti-inflammatory or immunosuppressant properties . Finally, 23 marine compounds were reported to act on a variety of molecular targets and thus could potentially contribute to several pharmacologic classes . Thus, as in 1998 and 1999, during 2000 pharmacologic research with marine chemicals continued to contribute potentially novel chemical leads to the ongoing global search for therapeutic agents in the treatment of multiple disease categories.

Vet Res Commun, 2003 Sep, 27(6), 475 - 83
Comparative plasma pharmacokinetics and tolerance of florfenicol following intramuscular and intravenous administration to camels, sheep and goats; Ali BH et al.; Florfenicol, a monofluorinated analogue of thiamphenicol, has a broad antibacterial spectrum . The pharmacokinetics of florfenicol was studied following a single intravenous (i.v.) or intramuscular (i.m.) injection at a dose of 20 mg/kg body weight in healthy male camels, sheep and goats . The concentration of florfenicol in plasma was determined using a microbiological assay . Pharmacokinetic analysis was performed using a two-compartment open model . Following i.m . administration, the maximum plasma concentration of florfenicol (Cmax) reached in camels, sheep and goats was 0.84 +/- 0.08, 1.04 +/- 0.10 and 1.21 +/- 0.10 microg/ml, respectively, the the time required to reach Cmax (t(max)) in the same three respective species was 1.51 +/- 0.14, 1.44 +/- 0.10 and 1.21 +/- 0.10 h . The terminal half-life (t(1/2)beta) and the fraction of the drug absorbed (F%) in camels, sheep and goats were 151.3 +/- 16.33, 137.0 +/- 12.16 and 127.4 +/- 11.0 min, and 69.20% +/- 7.8% , 65.82% +/- 6.7% and 60.88% +/- 5.9%, respectively . The MRT in the same three respective species was 4.01 +/- 0.45, 3.42 +/- 0.39 and 2.98 +/- 0.32 h . Following i.v . administration, the terminal half-life (t(1/2)beta) and total body clearance (Clbeta) in camels, sheep and goats were 89.5 +/- 9.2, 78.8 +/- 8.3 and 71.1 +/- 8.9 min and 0.33 +/- 0.04, 0.30 +/- 0.03 and 0.27 +/- 0.03 L/h per kg, respectively . The area under the curve (AUC(0-infinity)) and the mean residence time (MRT) in the same three respective species were 60.61 +/- 6.98, 62.45 +/- 6.56 and 74.07 +/- 7.85 microg/ml per h, and 2.71 +/- 0.31, 2.34 +/- 0.25 and 2.11 +/- 0.23 h . These data suggest that sheep and goats absorb and clear florfenicol to a broadly similar extent, but the rate and extent of absorption of the drug tends to be higher in camels . Drug treatment caused no clinically overt adverse effects . Plasma enzyme activities and metabolites indicative of hepatic and renal functions measured 1, 2, 4 and 7 days following the drug treatment were within the normal range, indicating that the drug is safe at the dose used.

G Ital Med Lav Ergon, 2003 Jul-Sep, 25(3), 369 - 70
{Effects on function of human lymphocytes exposed to electromagnetic fields with a frequency from 1,500 to 2,000 MHz}; Jirillo E et al.; Normal human peripheral blood lymphocytes were irradiated for 10 or 5 min with frequencies from 1.5 to 2.0 GHz . The frequency of 1.8 GHz overlaps that of mobile phones and leads to a significant reduction of the T-cell mediated antibacterial activity.

Pol J Pharmacol, 2003 Jul-Aug, 55(4), 613 - 8
Evaluation of ofloxacin penetration into the skin after a single oral dose assessed by cutaneous microdialysis; Bielecka-Grzela S et al.; An antibacterial drug can exert its therapeutic action if it is present in target tissue at proper concentration . Cutaneous microdialysis is a relatively new technique, which allows to determine drug concentration in the skin . The aim of the study was to evaluate the ofloxacin concentrations in plasma and skin following a single oral dose of 0.4 g . Drug concentration in the skin was assessed by applying cutaneous microdialysis . The penetration of the studied agent into dermal microdialysate was compared with its penetration into theoretical peripheral compartment . Maximum ofloxacin concentration in plasma was 9.26 micromol/l on average and was achieved after about 1.7 h . Mean peak concentrations in cutaneous microdialysate and in theoretical peripheral compartment were comparable (4.16 versus 4.50 micromol/l), but time to peak concentration in theoretical peripheral compartment was significantly longer than in microdialysates (5.8 and 2.0 h, respectively) . Degree of penetration into cutaneous microdialysate was about 0.54 . Cutaneous microdialysis seems to be a valuable technique to evaluate drug penetration into the skin.

Am J Dent, 2003 Aug, 16(4), 244 - 8
Effect of low-viscosity resin-based composite on the microleakage of cervical restorations; Kubo S et al.; PURPOSE: To investigate the effect of a low-viscosity resin-based composite (LVC) liner on the microleakage of cervical resin-based composites bonded with new adhesive systems . METHODS: 180 wedge-shaped cervical cavities on bovine incisors were treated with AQ Bond (all-in-one), ABF (experimental two-step self-etching primer containing antibacterial monomer) or Clearfil SE Bond (two-step self-etching primer) systems according to the manufacturers' instructions . Half of the treated cavities in each adhesive system were lined with an LVC (Protect Liner F) and filled with a hybrid resin-based composite (Clearfil AP-X) . Ten specimens from each group were immersed in 0.5% basic fuchsin solution immediately after finishing the restorations . The specimens to be subjected to thermocycling (5-60 degrees C, 15 seconds dwell time, 5,000 cycles) or to flexural load cycling (approximately 0.5 mm labio-lingual displacement at the incisal edge, 10,000 cycles, 1 Hz) prior to immersion in the dye solution were also prepared . The teeth were sectioned through the center of the restorations and the degrees of dye penetration were scored . The data were analyzed with the Mann-Whitney U-test or the Kruskal-Wallis test (P < 0.05) . RESULTS: The use of the LVC liner significantly improved marginal sealing of AQ Bond . However, the LVC liner could not prevent the deterioration in the marginal integrity caused by thermocycling or flexural load cycling . In the case of ABF, the use of the LVC liner showed a trend toward less microleakage . For Clearfil SE Bond, the LVC liner prevented the deterioration in the marginal seal caused by thermocycling.

Eur J Immunol, 2003 Nov, 33(11), 3146 - 53
Microbial Toll-like receptor ligands differentially regulate CXCL10/IP-10 expression in fibroblasts and mononuclear leukocytes in synergy with IFN-gamma and provide a mechanism for enhanced synovial chemokine levels in septic arthritis; Proost P et al.; The CXC chemokine IFN-gamma-inducible protein-10 (IP-10/CXCL10) activates CXC chemokine receptor 3 (CXCR3) and attracts activated T cells and natural killer cells . Peripheral blood mononuclear cells (PBMC) produce low but significant amounts of IP-10/CXCL10 protein upon stimulation with double-stranded (ds) RNA, the Toll-like receptor 3 (TLR3) ligand . IFN-gamma is a superior IP-10/CXCL10inducer . The bacterial TLR4 and TLR2 ligands, LPS and peptidoglycan (PGN), inhibit IFN-gamma- or dsRNA-dependent IP-10/CXCL10 production in PBMC, whereas IL-8/CXCL8 production was enhanced . In fibroblasts a different picture emerges with IFN-gamma inducing moderate and dsRNA provoking strong IP-10/CXCL10 production . Furthermore, treatment of fibroblasts with IFN-gamma in combination with bacterial LPS or PGN results in a synergistic production of IP-10/CXCL10 and IL-8/CXCL8 . The synergistic induction of IP-10/CXCL10 in fibroblasts is reflected by significantly enhanced IP-10/CXCL10 concentrations in synovial fluids of septic compared to osteoarthritis patients to reach on average higher levels than those of IL-8/CXCL8 . These high amounts of IP-10/CXCL10 produced by connective tissue fibroblasts not only attract CXCR3 expressing activated Th1 cells and natural killer cells to sites of infection but may also antagonize the CCR3 dependent attraction of Th2 lymphocytes and exert CXCR3-independent, defensin-like antibacterial activity.

J Dermatol, 2003 Sep, 30(9), 644 - 8
Topical antibacterial agents in dermatology; Singal A et al.; Topical antibacterials are being widely used for the treatment or prevention of superficial bacterial infections . Emergence of drug resistant mutant strains of microorganisms and development of irritant and allergic contact dermatitis is a common problem with many of the topical antibacterials . Topical antibacterials are being reviewed with special emphasis on their spectrum of activity, resistance patterns, contact sensitivity potential and clinical uses . Factors which help the physician to choose a particular antibacterial for the specific indication in order to have the maximum efficacy and minimum adverse effects are discussed.

Z Naturforsch {C}, 2003 Sep-Oct, 58(9-10), 687 - 90
Analysis of essential oil of Coridothymus capitatus (L.) and its antibacterial and antifungal activity; Goren AC et al.; The water-distilled essential oil the leaves of Coridothymus capitatus were analyzed by GC/MS and also analyzed by direct thermal desorption GC/MS . Comparison was made between two analyses techniques . The essential oil consisted mainly of monoterpenes 98.9%, while oxygenated hydrocarbons were identified as 55.6 % and non-oxygenated hydrocarbons as 43.6% . As major components were found carvacrol (35.6%), p-cymene (21.0%), thymol (18.6%), gamma-terpinene (12.3%), alpha-terpinene (3.2%), beta-myrcene (3.0%) and alpha-thujene (1.3%) by hydrodistillation and by the GC/MS method . The direct thermal desorption GC/MS analysis also showed the same major components, namely carvacrol (51.6%), thymol (21.7%), p-cymene (9.7%) gamma-terpinene (8.2%), alpha-terpinene (1.64%) . The essential oil of C . capitatus showed strong activity against S . aureus, P . vulgaris, P . aeruginosa, E . coli, K . pneumonia, B.

Z Naturforsch {C}, 2003 Sep-Oct, 58(9-10), 670 - 4
Antibacterial polyphenol from Erodium glaucophyllum; Gohar AA et al.; Geraniin and gallic acid were isolated from the alcohol extract of the aerial parts of Erodium glaucophyllum (Geraniaceae) . The identity of the compounds was verified through different physical and spectrometric methods . The antibacterial and antifungal activity of geraniin is presented.

J Nat Prod, 2003 Oct, 66(10), 1302 - 6
Annularins A-H: new polyketide metabolites from the freshwater aquatic fungus Annulatascus triseptatus; Li C et al.; Eight new polyketide metabolites, annularins A-H (1-8), along with the known compound (-)-(S)-p-hydroxyphenyllactic acid, were isolated from the organic extracts of the freshwater fungus Annulatascus triseptatus . Compounds 1-6 are 3,4,5-trisubstituted alpha-pyrones, and the fused bicyclic pyrone-furanone system in annularin F (6) has not been reported previously among natural products . Compounds 7 and 8 are 3,4-disubstituted alpha,beta-unsaturated gamma-lactones . Annularins A (1), B (2), C (3), and F (6) exhibited antibacterial activity.

Avian Dis, 2003, 47(3 Suppl), 817 - 22
Evaluation of pathogenic potential of avian influenza virus serotype H9N2 in chickens; Bano S et al.; Recently seven isolates of avian influenza virus (AIV) serotype H9N2 recovered from an outbreak of AI were analyzed on the basis of their biological and molecular characteristics . All the isolates belonged to the low-pathogenicity group of AIV . To further evaluate their pathogenic potential in association with other organisms, an isolate was inoculated experimentally in chickens using different routes and subsequently challenged with infectious bronchitis virus, Ornithobacterium rhinotracheale or Escherichia coli . The virus isolation and seromonitoring data revealed a significant role of Escherichia coli in aggravating the clinical condition of the birds earlier infected with AIV (H9N2) . The AIV-antigen was detected in lung, trachea, kidney, and cloacal bursa among the infected birds, using immunofluorescent antibody technique . In another experiment, chickens that were immunosuppressed chemically showed high mortality when challenged with AIV H9N2 . The results indicated that this low pathogenicity AIV (H9N2) isolate could produce severe infection depending on the type of secondary opportunistic pathogens present under field conditions . This may explain the severity of infection with the present H9N2 outbreak in the field . A prolonged antibacterial therapy in flocks infected with AIV H9N2 and use of oil-based vaccine at an early age in new flocks has helped to control this infection and the disease.

Przegl Lek, 2003, 60 Suppl 5, 54 - 7
{Bacterial infections in neutropenic patients with cancer}; Matysiak M; This paper shows the predisposing factors for infection in neutropenic patients with cancer, and the use of antibiotics in empirical antibacterial therapy . The role of glicopeptide and the fourth generation of cephalosporis in monotherapy and dualtherapy in empirical treatment of febrile neutropenia is also discussed.

Curr Opin Microbiol, 2003 Oct, 6(5), 431 - 8
Novel inhibitors of bacterial cell wall synthesis; Silver LL; Over the past forty years, efforts to discover antibacterials have yielded a wide variety of chemical structures, almost exclusively natural products, which inhibit many steps in cell wall synthesis . Although screening for new cell wall inhibitors has been continuous during that period, there have been few reports of new drugs . With the advent of genomics, high resolution X-ray crystallography and the recognition of the need for new antibiotics to combat resistant organisms, there has been a resurgence in interest in this validated target area.

Curr Opin Microbiol, 2003 Oct, 6(5), 427 - 30
Why is big Pharma getting out of antibacterial drug discovery?
Projan SJ.
Since the advent of the antibiotic era in the late 1940s drug discovery and development has evolved into an expensive, time consuming, cumbersome and bureaucratic process involving multiple interest groups such as pharmaceutical manufacturers, governmental regulatory authorities, patent officers, academic and clinical researchers and trial lawyers . It would seem that the least involved among the interest groups are the consumers of health care themselves . Politicians and the public alike complain loudly about drug prices although fewer and fewer new therapies are being developed . The cost and complexities of drug discovery and development have shifted the investment equation away from the development of drugs targeting short course therapies for acute diseases and towards long-term treatment of chronic conditions . Coupled with the failure of large investments into target-based approaches to produce novel antibacterial agents, companies large and small have exited from this field despite a growing clinical need.

Yakushigaku Zasshi, 2003, 38(1), 11 - 27
{A 50-year history of new drugs in Japan-the development and progress of anti-diabetic drugs and the epidemiological aspects of diabetes mellitus}; Ozawa H et al.; The development and progress of antidiabetic drugs (e.g., insulin preparations and hypoglycemic drugs) are retrospectively investigated in Japan . Their influences on the treatment of diabetes mellitus (DM) and its epidemiological aspects are also discussed . 1) Insulin preparations: Insulin was introduced for DM therapy in 1925, two or three years after its discovery in Canada . The preparations were raw extracts of bovine or porcine pancreas . These did not prevail widely in Japan because of the low incidence of DM before World Wan II . After the war, a shortage of mammalian materials compelled the use of fish pancreatic tissues such as bonito and/or tuna for insulin production . Insulin infection, so-called regular insulin, was first promoted in the 6th "Pharmacopoeia Japonica" (JP6) in 1951 and has been maintained to the present edition (JP14, 2001) . Although depot-type insulin preparations were developed in the USA and Europe during the war, the introduction of those preparations to Japan was delayed until 1951, when Protamine zinc insulin appeared . Globin zinc insulin and Isophane insulin were introduced for clinical use in 1952 and 1955, respectively . These were also adopted for JP7 (1961) . Biphasic-type insulin, which has a rapid onset and long duration of activity, appeared in 1965 . Purified preparations from bovine or porcine sources have been available since 1980, which might be a strong reason for the decrease in insulin allergy . Insulin from animal origin has been supplied for almost 60 years since its discovery . Amino acid sequences of insulins from various species of animals were determined by the pioneering studies of Sanger and his associates . Human insulin, which differs from porcine insulin by only one amino acid, was produced by Novo researchers in 1982 using a semi-synthetic method . Then the Lilly group soon succeeded in obtaining human insulin by recombinant DNA technology in the same year . Both products were introduced to Japan in 1985, and the recombinant products prevailed throughout the 1990s . Human insulin analogues (i.e., Insulin lispro and Insulin aspart) appeared in 2001 . These are applied for after-meal glycosmia owing to their ultrarapid onset of activity . Self-injection by DM patients was legalized in 1981 . To make the infection technique sure and easy, cartridge (pen-type) and disposable kit-type needles were devised in the 1990s . 2) Oral hypoglycemic drugs: Instead of the exclusive parenteral usage of insulins, there was also demand for oral dosage forms . The first of the sulfonyrlurea (SU) group, BZ-55, was used for DM clinically in 1955 in Germany . But it was soon withdrawn because of its antibacterial action . This led to the development of various SU groups . Tolbutamide (1956), chlorpropamide (1959), acetohexamide (1964) and tolazamide (1961) were introduced to Japan as first-generation SUs . Then glyclopyramide (Kyorin, 1965), glybenclamide (1971), gliclazide (1984) and glimepiride (1999) appeared as the second-generation SUs . These were used orally for Type 2 diabetes . Biguanide (BG) group, phenformin HC1 (1959), metformin HC1 (1961) and buformin HC1 (1961) had also been in use by oral treatment of Type 2 diabetes . SU appears to act by increasing the sensitivity of b-cells, which secrete insulin . BG probably exerts by increasing glucose transport across the membranes of target organs . 3) New types of antidiabetic drugs: a-Glucosidase inhibitors (i.e., acarbose: Bayer, 1993; and voglibose: Takeda, 1994) act on hyperglycemia after meals by decreasing glucose absorption . Thiazolidinedione compounds, such as troglitazone (Sankyo, 1995) and pioglitazone HC1 (Takeda, 1994) act by increasing the insulin sensitivity of the target tissues . These are useful for Type 2 DM patients when SUs are ineffective . Nevertheless, troglitazone was discontinued in 2000 due to severe liver damage . Nateglinide (Ajinomoto Co., 1999), which is a D-phenylalanine derivative acting similar to SUs, is useful orally for after-meal hyperglycemia of Type 2 diabetes . Epalrestat (Ono Yakuhin Co., 1992) is effective for diabetic neuropathy by reducing the formation of sorbitol . These anti-DM drugs were recently studied and developed in Japan . 4) The Japan Diabetes Society proposed a guideline on diagnostic criteria and treatment of diabetes mellitus (DM) in 1999 and revised it in 2002 . DM is classified as insulin-dependent DM (Type l) and non-insulin dependent DM (Type 2) . Type 1, juvenile onset DM, requires insulin therapy to prevent ketosis and to sustain life . Treatment of type 2, adult onset DM, is recommended as a step-by-step method, starting with dietary-exercise therapy, followed by oral hypoglycemic drugs and then insulin therapy . DM patients with complications should have a therapy devised to match their circumstances . 5) Epidemiological aspects: The mortality rate of DM compared to the time of drug appearance was traced from 1920 to 2000 . The curve goes down slowly in the time frame of World War II, but rises from 1950 to 1970 . The elevation could not be suppressed by the appearance of SUs, BGs or improved insulin preparations . The curve runs flat from 1980 to 1990, which might be related to the use of purified insulin or human insulin therapy . The mortality rate of DM indicates that death by hyperglycemic coma and other deaths resulting from complications are excluded . The survey of the principal cause of death by DM during the period of 1981-1990 indicates that the death rate due to hyperglycemic coma is only 1.7% of the total deaths caused by DM . The effect of drug therapy on all of the death resulting from DM is not detected . Hospital visitation and admission rates of the DM patients have been recorded since 1952 in Japan . This curve is rising continuously, and none of the antidiabetic drugs has been able to suppress it . These data show that the antidiabetic drugs relieve DM symptoms through their effective hypoglycemic actions, but that they cannot suppress the mortality rate of DM . It is possible that none of the drugs currently available can suppress the increasing tendency of DM patients.

Can J Microbiol, 2003 Jul, 49(7), 425 - 32
Shifts in community composition provide a mechanism for maintenance of activity of soil yeasts in the presence of elevated copper levels; Cornelissen S et al.; Soil dilution plates were prepared from different soil samples using a solid synthetic selective medium containing (i) . glucose as carbon source, (ii) . thymine as nitrogen source, (iii) . vitamins, (iv) . minerals, and (v) . chloramphenicol as antibacterial agent . Using the Diazonium Blue B colour reaction, it was found that both ascomycetous and basidiomycetous yeasts were able to grow on this medium . Subsequently, the medium was used to enumerate yeasts in soil microcosms prepared from four different soil samples, which were experimentally treated with the fungicide copper oxychloride, resulting in copper (Cu) concentrations of up to 1000 ppm . The selective medium supplemented with 32 ppm of Cu was used to enumerate Cu-resistant yeasts in the microcosms . The results showed that the addition of Cu at concentrations >or=approximately 1000 ppm did not have a significant effect on total number of yeasts in the soil . Furthermore, it was found that Cu-resistant yeasts were present in all the soil samples, regardless of the amount of Cu that the soil was challenged with . At the end of the incubation period, yeasts in the microcosms with zero and approximately 1000 ppm of additional Cu were enumerated, isolated, and identified with sequence analyses of the D1/D2 600-650 bp region of the large subunit of ribosomal DNA . Hymenomycetous species dominated in the control soil, while higher numbers of the urediniomycetous species were found in the soil that received Cu . These observations suggest that urediniomycetous yeasts may play an important role in re-establishing overall microbial activity in soils, following perturbations, such as the addition of Cu-based fungicides.

Adv Exp Med Biol, 2003, 530, 645 - 52
Tissue hypoxia during bacterial sepsis is attenuated by PR-39, an antibacterial peptide; James PE et al.; Endotoxin (a lipopolysaccharide (LPS) component of the Gram negative bacterial cell wall) induces sepsis in laboratory animals and is the cause of septic shock in patients . Tissues often develop necrotic regions, particularly in kidney and liver, thought to be directly the result of endotoxin-induced release of nitric oxide (NO) . These studies investigated the potential of PR-39, an antibacterial peptide, as an alternative treatment for sepsis . Our rationale for these experiments was based on the knowledge that PR-39 inhibits the superoxide-producing NADH/NADPH-oxidase system, and also inhibits NOS . In a mouse model of sepsis, we carried out EPR measurements of liver pO2 and NO simultaneously in vivo . Physiological parameters were also measured in these animals (blood pressure, heart rate) . NO levels in blood were measured by EPR analysis of red blood cell nitrosyl-hemoglobin . We found PR-39 alleviated endotoxin-induced liver hypoxia 6 hrs after treatment . Tissue NO was higher in the PR-39 + LPS group compared to LPS alone . Circulating levels of NO were the same in these groups . Taken together, these results suggest PR-39 is effective in improving survival following a septic episode . The exact mechanism is unclear, but increased NO as a result of decreased superoxide production seems to play an important role in alleviating tissue hypoxia.

Cent Afr J Med, 2002 Sep-Oct, 48(9-10), 105 - 8
A comparison of topical Phenytoin with Silverex in the treatment of superficial dermal burn wounds; Carneiro PM et al.; OBJECTIVE: To compare topical diphenylhydantion (Phenytoin) with silver sulphadiazine/chlorhexidine (Silverex) in terms of rate of wound healing, analgesic and antibacterial properties in small to moderate-sized (< 30% TBSA) superficial dermal (second degree) burn wounds . DESIGN: A prospective randomized controlled study . SETTING: Surgical wards, Muhimbili National Hospital from July 2000 to February 2001 . SUBJECTS: Sixty four patients with acute burns, 32 in each group . INTERVENTIONS: Study group treated by sprinkling Phenytoin powder and control group by sprinkling Silverex powder on the wounds for 14 days or until the wound epithelialised or was ready for skin grafting . The data collected included demographic characteristics of patients, aetiology of burn injury, circumstances of injury, site and extent of burns, pus discharge and smell from the wound, pain and discomfort from the wound, bacterial cultures of wound swabs, rate of reduction in wound size and outcome of treatment . RESULTS: The study enrolled 33 male and 31 female patients, 69% being children under five years of age . Hot liquids (80%) and open flames (20%) were the only causes of burns . In 97% of patients injury was due to domestic accidents . In half of the patients burns involved the trunk, and 52% of all patients had less than 15% total body surface burnt . Pus discharge was recorded in 59% of Phenytoin-treated and 75% in Silverex-treated patients while foul smell was noted in 19% and 31% of cases respectively . There were more negative bacterial wound cultures in Phenytoin-than Silverex-treated wounds on day five and day 10 of treatment, the difference being statistically significant (p < 0.01 and 0.001 respectively) . There was also a statistically significant difference in wound pain in favour of Phenytoin (p < 0.01) . There was no statistically significant difference in the rate of healing in the two groups . CONCLUSION: Phenytoin is a cheap and easy-to-use medicament, effective in suppressing burn wound bacteria and relieving pain thereby promoting healing, and may be advocated for the purpose in resource-scarce environments.






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